Candidoses B37.9

Authors: Prof. Dr. med. Peter Altmeyer, Angelika Németh

All authors of this article

Last updated on: 29.10.2020

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blastomycetica interdigital erosion; Candidamycosis; Candida mycosis; Candidamycosis interdigital; Candidasis; Candidates; Candidiasis; Candidosis; Granuloma candidamyceticum; Moniliasis; mucocutaneous candidiasis; Oidiomycosis; Oidomycosis; Oidosis; Thrush

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Localized, also disseminated infection of the skin and/or mucous membranes as well as systemic infections (especially in immunocompromised patients), caused by dimorphic fungi (yeast fungi), predominantly by Candida albicans.

Invasive (systemic) candidiasis mainly affects patients with additional risk factors (prolonged immunosuppression, neutropenia, long-term therapy with broad-spectrum antibiotics - very old - very young - very sick).

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Round to oval yeast fungi; usually present in sprouting form, in tissue (as invasively growing fungus) also as filamentary form (pseudomycelium).

The most common representative is C. albicans, as well as rarer species such as C. tropicalis, Candida guilliermondii, C. parapsilosis, C. krusei. The human pathogenic Candida species are common mucous membrane aprophytes. Candida albicans forms on very characteristic thick-walled permanent spores, the chlamydospores.

The differentiation of the different spores is very difficult. The differentiation of the different species can be carried out by means of a germ tube test or assimilation and fermentation tests or by molecular methods(PCR, MALDI-TOF test).

The following virulence factors are important for Candida albicans:

  • Colonisation: short regeneration times broad pH and temperature range adherence to epithelium (mannoproteins)
  • Tissue invasion: expression of lytic enzymes (the secretory aspartate proteinases (SAP) and the phospholipases- Calderone RA et al. 2001), formation of special morphological structures (germ tubes); alternation between unicellular yeast form and multicellular filamentous form (dimorphism).
  • Tissue persistence: "phenotypic switch" "antigenic mimicry" = masking with endogenous structures, the ability to form biofilms.

Note: Secretory aspartate proteinases (SAP) are expressed differently under variable environmental conditions and in different types of infection (Staib P et al. 2008). There are currently 10 SAP genes known whose diverse functions are important for the virulence of C. albicans. In addition to tissue invasion, they also play an important role in adhesion, biofilm formation, phenotypic switching and dimorphism (Staib P et al. 2008). The ability of C. albicans to switch between two different morphological forms, unicellular yeast form and multicellular filamentous form (hyphe) is considered to be an essential virulence factor (Dimorphism - Ramage G et all. (2005). The change between the different growth forms is possible in response to different environmental conditions (Ernst JF 2000). A special feature ofC. albicans and C. dubliniensis is the formation of pseudohyphs (germ tube formation) and chlamydospores under specific conditions (Calderone RA et al. 2001; Staib P et al. 1999). This special ability is used for differentiation from other Candida species. Hyphae formation is considered to be of essential importance, since this growth form is predominantly found in tissue invasion.

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Yeasts of the genus Candida are found as saprophyte in low concentrations in a part of the healthy population:

  • stool > 50%.
  • Oropharynx 30%
  • vagina 25%
  • Skin, rarely without symptoms of disease.

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Infection with Candida, mostly Candida albicans. Systemic predisposing factors (very old, very young, very sick) include:

diabetes mellitus, obesity, antibiotic therapy, immune deficiency, pregnancy, Cushing's disease, Addison's disease, hypoparathyroidism, hypothyroidism, immune deficiencies as a result of immunosuppressive therapy(glucocorticoid therapy, cytostatic therapy) or HIV infection, taking ovulation inhibitors, working in a humid environment, wearing occluding clothing for long periods.

Occurrence of invasive Candida infections are almost exclusively observed in immunocompromised persons!

Clinical features
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S.u. and the respective clinical pictures.

Candidastomatitis or esophagitis (possibly dysphagic symptoms) are important indications of a profound immunosuppression (e.g. HIV infection).

Systemic candida infections: Patients with complex immunosuppressive disorders (possibly in combination with neutropenia, long-term antibiotic therapy, chemotherapy) may develop candida fungaemia and disseminated visceral candidosis (septicaemia) with infestation of the liver, spleen, kidneys, ocular fundus (cotton wool foci), endocarditis (I33.0) or osteomyelitis (M86.-).

A typical clinical picture for patients with long-term neutropenia (e.g. after stem cell transplantation) is hepatosplenic candidiasis with multiple splenic and hepatic abscesses (van Prehn J et al. 2017).

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Clinical symptoms indicating candidosis.

Mycological diagnosis; the shoot cells typical for yeasts become visible in a native preparation on KOH-basis. Exclusion of bacterial infections.

Culture: In view of the resistance of some Candida species (e.g. Candida glabrata or other non-albicans species) to various bacterial pathogens, a culture is recommended. Antimycotic agents, the identification of the species is useful. If only one single colony is detected in culture, a single commensal yeast cell is suspected. The cultural identification of a species is still necessary for all chronic relapses, especially in immunocompromised patients.

Peptide nucleic acid fluorescence interest situ hybridization (PNA-FISH) method: This method allows a faster differentiation of C. albicans and C. non-albicans species compared to the classical diagnostic method of germ tube formation.

Furthermore, the Candida species can also be distinguished biochemically by evaluating different assimilation profiles (Pappas PG 2006).

PAS-stains: Detection of Candida in tissue sections using periodic acid-ship (PAS) staining.

Systemic Candida infection: The detection of a systemic Candida infection is often difficult, because on the one hand the clinical signs are unspecific and on the other hand the detection of yeast cells from blood culture is often not possible. Even in cases of disseminated invasive candidosis, for example in immunocompromised patients, blood cultures are negative in more than 50 % (Holzheimer RG et al. 2002).

Serological antibody detection is only of limited use due to insufficient sensitivity and specificity (Ruhnke M et al. 2002).

A wood-light examination is unsuitable for the detection of candidosis.

Differential diagnosis
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Bacterial infections caused by streptococci or staphylococci; erythrasma; intertrigo; pustulosis of other genesis.

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With the increasing number of immunocompromised patients and the introduction of new therapeutic methods, there has also been an increase in life-threatening fungal infections. Another problem was the increase in resistance to the available antifungal drugs.

Two main groups of antimycotics, polyenes and azoles, have the cell membrane as their target structure, as do allylamines. The only systemically applicable polyene is Amphotericin B, which was the only available antimycotic in the therapy of systemic mycoses for almost 30 years.

The mechanism of action of this substance class is based on a binding to the sterol/ergosterol of the cell membrane, which leads to pore formation. The resulting increase in permeability of the cell membrane leads to cell death. Secondary resistances to Amphotericin B or Nystatin are rare. However, some species like C. lusitaniae and C. guilliermondii are primarily resistant to Amphotericin B. The mechanism of polyene resistance in Candida seems to be associated with a reduction of the ergosterol content.

A problem of Amphotericin B is the side effects it causes (especially nephrotoxicity). By using the newer liposomal Amphotericin B preparations, nephrotoxicity could be reduced with comparable effectiveness.

The imidazoles (e.g. ketoconazole) and triazoles (e.g. fluconazole) inhibit the ergosterol synthesis by blocking the cytochrome P450 dependent enzyme 14α-demethylase. The result is an accumulation of toxic ergosterol precursors, a decrease in ergosterol with resulting disruption of the membrane structure and inhibition of some membrane-bound enzymes. The widespread and, especially in HIV patients, long-term use of azoles has led to an accumulation of infections by azole-resistant Candida strains and to a selection of Candida species with intrinsic resistance to fluconazole such as C. krusei and C. glabrata. Fluconazole is the most commonly used Candida species in the azole group of substances.

In the meantime, various mechanisms leading to resistance have been identified:

  • Upregulation of multidrug efflux transporter genes (ABC transporter genes and major facilitator gene)
  • Amino acid substitution in the Erg11p protein (=target structure of the azoles)
  • Upregulation of the ERG11 gene
  • Changes in the sterol composition due to a lack of activity of sterol desaturase encoded by the Erg3 gene

Voriconazole, a representative of the triazoles, has a broad spectrum of activity that includes both Candida and Aspergillus (Walsh TJ et al (2002). It is approved in Europe for the treatment of severe, fluconazole-resistant Candida infections, among others. In November 2006, posaconazole was approved for prophylaxis and first-line therapy of oropharyngeal candidiasis. In European studies, the vast majority of Candida isolates showed high sensitivity to these azoles (Tortorano AM et al.2006).

Allylamines: The allylamines with their main representative terbinafine also intervene in the ergosterol biosynthesis, their target structure is squalene epoxidase. They are used in the treatment of dermatophyte infections. Resistances in humans are not known so far.

5-Flucytosine: 5-flucytosine, a pyrimidine analogue with fungistatic effect is converted in the cell by cytosine permease into 5-fluoruracil; this interferes with nucleic acid and protein synthesis. In some Candida species, including C. albicans serotype B, C. glabrata and C. krusei, primary resistances are often found (Perea S et al. 2002). Since secondary resistances also occur rapidly, 5-flucytosine is mainly used in combination with amphotericin B or fluconazole. In addition to Candida, Cryptococcus Neoformans also belongs to the spectrum of activity.

Echinocandins: Echinocandins are the newest substance class with a completely new point of attack. They belong to the lipopeptides, which are built up from a cyclic hexapeptide with N-linked fatty acid side chains. The echinocandins unfold their antimycotic effect by non-competitive inhibition of the β-1,3-glucan synthetase and thus disturb the cell wall biosynthesis (Ghannoum MA et al. 1999). Caspofungin was the first representative of this substance group to be approved by the EMEA in 2001. Various studies have shown a good efficacy of caspofungin compared to amphotericin B and fluconazole in the therapy of oropharyngeal and esophageal candidiasis (Villanueva A et al. 2002). Of clinical importance is also the good efficacy of caspofungin against azole-resistant Candida. All in all, the echinocandins can be regarded as progress in antimycotic therapy. The protein Fks1p, the catalytic subunit of the β-1,3-glucan synthetase, is probably the target structure of the echinocandins (Douglas CM et al. 1997).

S.further under: Candidosis, intertriginous; Candidosis, enteral; Candida sepsis; Candida granuloma; Candida of the oral mucosa; Vulvovaginal candidiasis;

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