Candida glabrata- An Overview

Candida glabrata is a type of yeast that belongs to the genus Candida, which includes more than 200 species of fungi that can cause infections in humans and animals. Candida glabrata was previously known as Torulopsis glabrata, and it is closely related to the baker`s yeast Saccharomyces cerevisiae.

Candida glabrata is one of the most common candida species, living commensally in the human host. It does not cause disease in healthy individuals, but it can become opportunistic and cause infections in people with weakened immune systems or other risk factors. These infections can range from superficial (such as oral, esophageal, vaginal, or urinary) to systemic (such as bloodstream or organ infections), and they are often difficult to treat due to the high resistance of Candida glabrata to many antifungal drugs.

Candida glabrata is responsible for about 15-30% of all cases of candidemia (bloodstream infection by candida species), which is a serious and potentially life-threatening condition. Candidemia is more common in hospitalized patients, especially those who have undergone surgery, chemotherapy, organ transplantation, or have indwelling catheters or devices. Candidemia can also occur in patients with diabetes mellitus, HIV/AIDS, cancer, or other chronic diseases that impair the immune system.

Candida glabrata can also cause infections of the mucosal surfaces, such as the mouth, throat, esophagus, vagina, or urinary tract. These infections are usually less severe than systemic ones, but they can cause discomfort, pain, inflammation, and sometimes complications such as abscesses or perforations. The most common mucosal infection caused by Candida glabrata is vulvovaginal candidiasis (VVC), which affects about 75% of women at some point in their lives. VVC can cause itching, burning, discharge, and sometimes pain during sexual intercourse or urination. VVC can be recurrent or chronic in some women, especially those who have diabetes mellitus, use oral contraceptives or antibiotics, or have hormonal imbalances.

The diagnosis of Candida glabrata infections can be challenging, as it requires the isolation and identification of the yeast from the infected site or blood sample. The morphology and culture characteristics of Candida glabrata are similar to other candida species, so specialized tests such as chromogenic media or molecular methods are needed to differentiate them. The treatment of Candida glabrata infections depends on the type and severity of the infection, the patient`s condition and risk factors, and the susceptibility of the yeast to antifungal drugs. The main classes of antifungal drugs used to treat Candida glabrata infections are azoles (such as fluconazole), polyenes (such as amphotericin B), and flucytosine. However, Candida glabrata has intrinsic or acquired resistance to many of these drugs, especially azoles, which limits the therapeutic options and increases the risk of treatment failure and relapse.

The prevention and control of Candida glabrata infections require a combination of measures that aim to reduce the exposure and colonization of the yeast in the host, enhance the host`s immune response and defense mechanisms against the yeast, and optimize the use and selection of antifungal drugs to prevent resistance development and spread. Some of these measures include:

• Practicing good hygiene and sanitation practices to avoid contamination and transmission of the yeast
• Avoiding unnecessary or prolonged use of antibiotics or corticosteroids that can disrupt the normal flora and favor the overgrowth of Candida glabrata
• Using barrier methods such as condoms or diaphragms to prevent sexual transmission of Candida glabrata
• Maintaining a healthy diet and lifestyle that can boost the immune system and prevent chronic diseases that predispose to Candida glabrata infections
• Seeking medical attention promptly if symptoms of Candida glabrata infection occur and following the prescribed treatment regimen
• Monitoring the response and outcome of treatment and reporting any adverse effects or signs of resistance to antifungal drugs

Candida glabrata is an emerging pathogen that poses a significant challenge for clinical management and public health. It is important to increase the awareness and knowledge about this yeast among health professionals and patients alike, as well as to promote research and innovation in developing new strategies for diagnosis, treatment, prevention, and control of Candida glabrata infections.

Candida glabrata is a ubiquitous yeast that can be found in various habitats, both in the human body and in the environment. Some of the common habitats of C. glabrata are:

• The human body: C. glabrata is a commensal organism that normally lives as part of the microflora of the gastrointestinal tract, the oral cavity, the genitourinary tract, and the respiratory tract of healthy individuals. However, in immunocompromised or debilitated hosts, C. glabrata can become an opportunistic pathogen that causes infections of the mucosal surfaces or systemic infections by entering the bloodstream.
• The environment: C. glabrata can persist on environmental surfaces for several months, such as hospital equipment, medical devices, catheters, and prosthetic materials. These surfaces can serve as sources of transmission and infection for susceptible patients. C. glabrata can also be isolated from soil, water, plants, and animals.

Candida glabrata is a highly adaptable yeast that can survive and grow in different conditions, such as high temperature, low pH, high salinity, and presence of antifungal agents. This ability contributes to its widespread distribution and its emergence as a significant cause of candidiasis in humans.

Candida glabrata is a yeast species that belongs to the genus Candida. It is one of the most common candida species, living commensally in the human host. However, it can also cause candidiasis in persons with underlying conditions that suppress their immune functions . Here is a description of Candida glabrata`s morphology:

• Cellular Shape: Candida glabrata cells are typically ovoid or spherical in shape, similar to other yeast cells. When dividing, it may appear as single cells or form brief chains or clusters .
• Cell Size: The blastoconidia of C. glabrata are very small, 1 to 4 μm in diameter, considerably smaller than Candida albicans blastoconidia, which are 4 to 6 μm .
• Cell Wall: The cell wall of C. glabrata is composed of glucan, mannoprotein and chitin, similar to other candida species. However, C. glabrata has a higher content of β-1,3-glucan and a lower content of β-1,6-glucan than C. albicans . The cell wall also contains phospholipomannan, a glycolipid that plays a role in adhesion and immune evasion .
• Colony Morphology: On Sabouraud dextrose agar, C. glabrata forms glistening, smooth, cream-colored colonies that are similar to other candida species, except their relatively small size . On Chromagar, a differential medium for candida species, C. glabrata produces colonies that appear pink to purple, in contrast to C. albicans colonies, which appear green to blue-green .
• Dimorphism: Unlike other candida species that are dimorphic in nature, C. glabrata is nondimorphic, existing only as small blastoconidia. It is the only candida species that does not form pseudohyphae at temperatures higher than 37°C .
• Genome: C. glabrata has a haploid genome with 13 chromosomes and a total size of about 12 Mb. It has small RNA subunits (18S and 5S), unlike other candida species that have large RNA subunits (25S and 5.8S) . C. glabrata is evolutionarily closer to the non-pathogenic yeast Saccharomyces cerevisiae than to the most prevalent candida pathogen, C. albicans .

Figure: Candida glabrata – 1600x (Source: BCarver1) and Candida glabrata yeast under an electron microscope. The figure shows two single cells and two mother-daughter pairs during the budding process. Source: Khadija Mohamed Ahmad (Researchgate).

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\caption{Candida glabrata – 1600x (Source: BCarver1) and Candida glabrata yeast under an electron microscope. The figure shows two single cells and two mother-daughter pairs during the budding process. Source: Khadija Mohamed Ahmad (Researchgate).}
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Candida glabrata is typically a commensal of human mucosal tissues; however, in the current era of widespread human immunodeficiency due to various causes (such as therapeutic immunomodulation, longer survival with various comorbidities such as diabetes, and HIV infection), C. glabrata is frequently the second or third most common opportunistic pathogen causing candidiasis . Candidiasis is a clinical condition that can affect any organ system, but most commonly involves the bloodstream, the urogenital tract, and the oral cavity.

The pathogenesis of C. glabrata involves several factors that enable it to adhere to host surfaces, evade host defenses, and cause tissue damage. Some of these factors are:

• Adherence: C. glabrata can bind to various host receptors, such as fibronectin, laminin, collagen, and epithelial cells . This facilitates its colonization and invasion of host tissues. C. glabrata also produces extracellular matrix (ECM) components that enhance its adherence and biofilm formation.
• Biofilm formation: C. glabrata can form biofilms on both biotic and abiotic surfaces, such as mucosal membranes, indwelling medical devices, and catheters . Biofilms are complex communities of microorganisms embedded in a self-produced matrix that protect them from host immune responses and antifungal agents.
• Replicative aging: C. glabrata undergoes asymmetric cell division, resulting in a mother cell and a daughter cell. The mother cell accumulates cellular damage over time and eventually dies, while the daughter cell remains young and healthy. This process of replicative aging allows C. glabrata to adapt to changing environmental conditions and stressors.
• Hydrolytic enzymes: C. glabrata produces various enzymes that can degrade host tissues and facilitate its dissemination. These include phospholipases, proteases, and hemolysins . Phospholipases can damage cell membranes and cause cell lysis. Proteases can degrade host proteins and ECM components. Hemolysins can lyse red blood cells and release iron for fungal growth.
• Iron regulation: C. glabrata can acquire iron from different sources, such as transferrin, lactoferrin, hemoglobin, heme, and ferritin. Iron is essential for fungal growth and metabolism. C. glabrata can also regulate its iron uptake and storage according to the availability of iron in the environment.
• Genetic mutations: C. glabrata has a high rate of genetic mutations that confer resistance to antifungal agents, especially azoles . These mutations affect the target enzymes of azoles (such as lanosterol 14-alpha-demethylase), the efflux pumps that expel azoles from the cell (such as ATP-binding cassette transporters), and the transcription factors that regulate the expression of resistance genes (such as PDR1) .

These factors contribute to the pathogenicity and virulence of C. glabrata in causing candidiasis in immunocompromised hosts. The treatment of C. glabrata infections can be challenging due to its intrinsic or acquired resistance to antifungal agents. Therefore, prevention and control measures are important to reduce the risk of infection and transmission.

Candida glabrata is a yeast with low intrinsic virulence, but it can cause serious infections in immunocompromised hosts. Some of the virulence factors that contribute to its pathogenicity are:

• Adherence factors: C. glabrata can adhere to epithelial and endothelial cells of the host tissues, as well as to medical devices such as catheters and prosthetic valves. This facilitates its colonization and invasion of the host. C. glabrata has several cell surface proteins that act as adhesins, such as Epa1, Epa6, Epa7, Awp2, and Als3 .
• Enzyme secretion: C. glabrata can secrete hydrolytic enzymes that help it to evade host defense reactions and damage host tissues. These enzymes include phospholipases, proteases, and haemolysins .
• Biofilm formation: C. glabrata can form biofilms on various surfaces, such as mucosal membranes, skin, and medical devices. Biofilms are complex communities of microorganisms embedded in a matrix of extracellular polymeric substances. Biofilms confer resistance to antifungal drugs, host immune system, and environmental stresses .
• Presence of a stable cell wall: C. glabrata has a cell wall composed of polysaccharides, proteins, and lipids that protect it from physical and chemical damage. The cell wall also modulates the interaction with the host immune system by masking or exposing antigens .
• Novel hybrid iron regulation and acquisition strategies: C. glabrata can acquire iron from various sources in the host environment, such as heme, transferrin, lactoferrin, and siderophores. Iron is essential for the growth and metabolism of C. glabrata. C. glabrata can also regulate its iron homeostasis by sensing the iron availability and adjusting its gene expression accordingly .
• Phenotypic switching: C. glabrata can switch its colony phenotype without affecting its genotype. This allows it to adapt to different environmental conditions and evade host immune recognition. Phenotypic switching can affect the morphology, color, size, shape, and surface properties of C. glabrata colonies .

Candida glabrata can cause both superficial and systemic infections, depending on the host`s immune status and the site of colonization. The most common clinical manifestations of C. glabrata infections are:

• Superficial infection. C. glabrata can cause symptomatic mucosal infection in the oropharynx, esophagus, and vagina, especially in HIV/AIDS patients and other immunocompromised patients. Oropharyngeal candidiasis is associated with acute pseudomembranous candidiasis, commonly known as oral thrush. It is the first sign of HIV infection, and progressive infection to AIDS, showing signs of asymptomatic erythematous forms. Esophageal candidiasis is associated with the disease dissemination from the oropharyngeal lining. Vulvovaginal candidiasis is common in women, pregnant women, diabetic patients, associated with mild to moderately severe candidiasis. C. glabrata can also cause urinary tract candidiasis, also known as candiduria, which is common in hospitalized patients with invasive catheters, diabetes mellitus patients, the elderly, and debilitated patients under antibacterial medications. However, there are no complicated hematogenous infections of the urinary tract are linked to C. glabrata.

• Systemic candidiasis. C. glabrata rarely causes systemic candidiasis, but it can disseminate to the bloodstream and other organs in immunocompromised patients, such as those with prolonged hospitalization, cancer chemotherapy, organ transplantation, or long-term administration of antibacterial agents and fluconazole antifungals . C. glabrata is one of the most common causes of candidemia, which is the presence of Candida in the blood. Candidemia is associated with persistent fever, deteriorating conditions, and unresponsiveness to antifungal agents . Fungemia is commonly caused by C. glabrata. C. glabrata can also cause acute hematogenous candidiasis, which is a Candida infection that spreads through the bloodstream to other organs of the body, such as the brain (causing meningitis), the heart (causing endocarditis), the bones (causing osteomyelitis), or the liver and spleen (causing chronic disseminated candidiasis).

To diagnose Candida glabrata infections, healthcare providers rely on various methods, such as:

• Staining and microscopic examination. A sample of the infected site, such as a swab, a wash, or a blood sample, is stained with potassium hydroxide (KOH) and examined under a microscope. C. glabrata appears as small, round yeast cells that are 1 to 4 μm in diameter. They do not form pseudohyphae or germ tubes like other Candida species.
• Cultural examination. A sample of the infected site is inoculated on a suitable medium, such as Sabouraud dextrose agar or CHROMagar Candida. On Sabouraud dextrose agar, C. glabrata forms smooth, cream-colored colonies that are smaller than other Candida species. On CHROMagar Candida, a differential medium for Candida species, C. glabrata produces pink to purple colonies, while C. albicans produces green to blue-green colonies .
• Biochemical tests. C. glabrata can be differentiated from other Candida species by its ability to ferment and assimilate only glucose and trehalose. It does not produce urease or phospholipase like other Candida species.
• Molecular-based tests. These tests use DNA analysis to identify and differentiate C. glabrata from other Candida species and strains. Some of the molecular-based tests include restriction fragment length polymorphism (RFLP), pulse-field gel electrophoresis (PFGE), electrophoretic karyotyping (EK), random amplified polymorphic DNA (RAPD), and DNA probing. These tests can also help in detecting antifungal resistance and epidemiological surveillance of C. glabrata infections.

The treatment of Candida glabrata infections depends on the type and severity of the infection, the underlying health condition of the patient, and the susceptibility of the fungus to antifungal drugs. In general, antifungal medications are the mainstay of treatment for Candida glabrata infections. However, some strains of Candida glabrata may be resistant to certain antifungal drugs, especially fluconazole, which is commonly used for Candida infections. Therefore, antifungal susceptibility testing is recommended to guide the choice of therapy.

Some of the antifungal drugs that may be used to treat Candida glabrata infections are:

• Fluconazole. This is an oral or intravenous drug that belongs to the azole class of antifungals. It works by inhibiting the synthesis of ergosterol, a component of fungal cell membranes. Fluconazole is effective for treating oropharyngeal, esophageal, vaginal, and urinary tract infections caused by Candida glabrata . However, fluconazole resistance is common among Candida glabrata isolates, especially in patients who have received prior fluconazole therapy or have a weakened immune system. Therefore, higher doses of fluconazole may be required for treating susceptible Candida glabrata infections, and alternative drugs may be needed for resistant strains.
• Amphotericin B. This is an intravenous drug that belongs to the polyene class of antifungals. It works by binding to ergosterol and creating pores in fungal cell membranes, leading to cell death. Amphotericin B is effective for treating systemic and invasive Candida glabrata infections, such as candidemia, endophthalmitis, meningitis, osteoarticular infections, and chronic disseminated candidiasis . Amphotericin B has a broad spectrum of activity against Candida species and is rarely associated with resistance. However, amphotericin B has significant side effects, such as nephrotoxicity, infusion-related reactions, and electrolyte disturbances. Therefore, amphotericin B is usually reserved for severe or life-threatening infections or when other antifungals are not available or effective.
• Flucytosine. This is an oral or intravenous drug that belongs to the pyrimidine analog class of antifungals. It works by interfering with fungal DNA and RNA synthesis. Flucytosine is effective for treating systemic and invasive Candida glabrata infections, especially in combination with amphotericin B . Flucytosine has a narrow spectrum of activity against Candida species and may be associated with resistance. Therefore, flucytosine is not used as monotherapy for Candida glabrata infections but as an adjunctive agent to enhance the efficacy and reduce the toxicity of amphotericin B . Flucytosine may also cause side effects such as bone marrow suppression, hepatotoxicity, and gastrointestinal disturbances.
• Echinocandins. These are intravenous drugs that belong to the lipopeptide class of antifungals. They work by inhibiting the synthesis of beta-glucan, a component of fungal cell walls. Echinocandins are effective for treating systemic and invasive Candida glabrata infections, such as candidemia and intra-abdominal abscesses . Echinocandins have a broad spectrum of activity against Candida species and are less likely to cause resistance than azoles. However, echinocandins may be less effective than amphotericin B for treating central nervous system or eye infections caused by Candida glabrata. Echinocandins may also cause side effects such as infusion-related reactions, hepatotoxicity, and rash. The echinocandins available for clinical use are caspofungin, micafungin, and anidulafungin.
• Voriconazole. This is an oral or intravenous drug that belongs to the azole class of antifungals. It works by inhibiting the synthesis of ergosterol. Voriconazole is effective for treating systemic and invasive Candida glabrata infections that are resistant to fluconazole or other azoles . Voriconazole has a broad spectrum of activity against Candida species and may be more potent than fluconazole against Candida glabrata. However, voriconazole may also cause side effects such as hepatotoxicity, visual disturbances, skin reactions, and drug interactions.

The duration of treatment for Candida glabrata infections varies depending on the type and severity of the infection, the response to therapy, and the resolution of underlying risk factors. In general, treatment should be continued until clinical improvement and negative cultures are achieved .

The prevention and control of Candida glabrata infections involve reducing the exposure to risk factors such as antibiotics, immunosuppressive drugs, indwelling devices, surgery, or hospitalization. In addition, prophylactic antifungal therapy may be considered for high-risk patients who are expected to have prolonged neutropenia or who have received organ transplantation .

Candida glabrata is a common cause of candidiasis in humans that can affect various parts of the body. The treatment of Candida glabrata infections requires antifungal medications that are effective against this fungus and its possible resistance mechanisms. Antifungal susceptibility testing is recommended to guide the choice of therapy. The prevention and control of Candida glabrata infections depend on reducing the exposure to risk factors and providing prophylactic antifungal therapy for high-risk patients.

Candida glabrata infections can be difficult to treat due to its high resistance to some antifungal medications, especially fluconazole. Therefore, prevention and control measures are important to reduce the risk of infection and transmission. Some of the prevention and control strategies are:

• Discontinuing or minimizing the use of catheters, intravenous lines, and other invasive devices that can introduce Candida into the bloodstream or the urinary tract .
• Prophylactic treatment with antifungal agents in hospitalized patients who are at high risk of developing candidemia or invasive candidiasis, such as those with neutropenia, hematologic malignancies, organ transplantation, or major surgery.
• Avoiding unnecessary or prolonged use of antibiotics that can disrupt the normal flora and favor the growth of Candida.
• Practicing good hygiene and sanitation practices to prevent the spread of Candida from person to person or from contaminated surfaces.
• Maintaining a healthy immune system by eating a balanced diet, getting enough sleep, managing stress, and avoiding smoking and excessive alcohol consumption.
• Seeking medical attention promptly if symptoms of Candida infection occur, such as oral thrush, vaginal discharge, burning urination, fever, or chills.
• Following the prescribed treatment regimen and completing the course of antifungal therapy to prevent relapse or resistance .
• Monitoring the susceptibility of Candida isolates to antifungal agents and reporting any cases of resistance to public health authorities.

Candida glabrata is a common and potentially serious cause of fungal infections in humans. By following these prevention and control measures, the incidence and severity of Candida glabrata infections can be reduced.

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