Candidoses B37.9

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).

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

Most frequent representative is C. albicans, besides rarer kinds like C. tropicalis, C. guilliermondii, C. parapsilosis, C. krusei. The human pathogenic Candida species are common mucosal saprophytes. Candida albicans forms on very characteristic thick-walled permanent spores, the chlamydospores.

The differentiation of the versch. Differentiation of the various species can be carried out by means of germ tube tests, assimilation and fermentation tests or molecular methods(PCR, MALDI-TOF test).

The following virulence factors are important for Candida albicans:

• Colonization: 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 particular 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 differentially expressed under variable environmental conditions and in different types of infection (Staib P et al. 2008). Currently, 10 SAP genes are known whose diverse functions are significant for C. albicans virulence. In addition to tissue invasion, they also play important roles in adhesion, biofilm formation, phenotypic switching, and dimorphism, among others (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 a major virulence factor (dimorphism - Ramage G et all. (2005). Switching between the different growth forms is possible in response to different environmental conditions (Ernst JF 2000). A distinctive feature ofC. albicans and C. dubliniensis is the formation of pseudohyphae (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. Hyphal formation is considered to be of major importance, as this form of growth is predominantly found during tissue invasion.

A distinction is made:

I. Candidosis of the skin:

• Intertriginous candidiasis (Candida intertrigo)
• Interdigital candidiasis
• paronychia candidamycetica
• folliculitis barbae candidamycetica
• Auditory canal candidosis
• S.a. Diaper dermatitis
• S.a. under Perlèche

II Candidosis of the mucous membrane:

• Vulvovaginal candidiasis
• balanitis candidamycetica
• Enteric candidiasis
• candidiasis of the oral mucosa
• Chronic Mucocutaneous Candidosis
• Candida sepsis
• Candida granuloma
• Urethritis candidamycetica.

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

• Stool > 50%
• Oropharynx 30%
• Vagina 25%
• Skin, more rarely without symptoms of disease.

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!

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).

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.

Bacterial infections due to streptococci or staphylococci; erythrasma; intertrigo; pustulosis of other etiology.

With the increasing number of immunocompromised patients and the introduction of new therapeutic methods, there was also an increase in life-threatening fungal infections. Also problematic was the increase in resistance to available antifungal agents.

Two main groups of antifungal agents, polyenes and azoles, target the cell membrane, as do allylamines. The only polyene that can be used systemically is amphotericin B, which was the only available antifungal agent in the therapy of systemic mycoses for almost 30 years.

The mechanism of action of this class of compounds is based on binding to the sterol/ergosterol of the cell membrane, resulting in pore formation. The resulting increase in permeability of the cell membrane leads to cell death. Secondary resistance to amphotericin B or to nystatin is rare. However, some species such as C. lusitaniae and C. guilliermondii are primarily resistant to amphotericin B. The mechanism of polyene resistance in Candida appears to be associated with a reduction in ergosterol content.

One problem with amphotericin B is the side effects it causes (especially nephrotoxicity). The use of the newer liposomal amphotericin B preparations has reduced nephrotoxicity, with comparable efficacy.

The imidazoles (e.g., ketoconazole) and triazoles (e.g., fluconazole) inhibit ergosterol synthesis by blocking the cytochrome P450-dependent enzyme 14α-demethylase. This results in accumulation of toxic ergosterol precursors, decrease in ergosterol with resulting disruption of 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 of the azole substance group against Candida infections.

Several mechanisms leading to resistance have now been identified:

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

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

Allylamines: Allylamines with their main representative terbinafine also interfere with ergosterol biosynthesis, their target being squalene epoxidase. They are used in the treatment of infections by dermatophytes. Resistance has not been reported in humans to date.

5-Flucytosine: 5-Flucytosine, a pyrimidine analog with fungistatic activity is converted to 5-fluorouracil in the cell by cytosine permease; this interferes with nucleic acid and protein synthesis. In some Candida species, including C. albicans serotype B, C. glabrata, and C. krusei, primary resistance is not uncommon (Perea S et al. 2002). Since secondary resistance also occurs rapidly, 5-flucytosine is predominantly used in combination with amphotericin B or fluconazole. The spectrum of activity includes not only Candida but also Cryptococcus Neoformans.

Echinocandins: Echinocandins are the latest class of substances with a completely new point of attack. They are lipopeptides composed of a cyclic hexapeptide with N-linked fatty acid side chains. Echinocandins exert their antifungal activity by non-competitive inhibition of β-1,3-glucan synthetase, thereby interfering with cell wall biosynthesis (Ghannoum MA et al. 1999). Caspofungin, the first representative of this substance group, was approved by the EMEA in 2001. Various studies have demonstrated good efficacy of caspofungin compared with amphotericin B and fluconazole in the treatment of oropharyngeal and esophageal candidiasis (Villanueva A et al. 2002). Also of clinical importance is the good efficacy of caspofungin against azole-resistant Candida. Overall, echinocandins can be considered an advance in antifungal therapy. The protein Fks1p, the catalytic subunit of β-1,3-glucan synthetase, is thought to be the target of the echinocandins (Douglas CM et al 1997).

S.further under: candidiasis, intertriginous; candidiasis , enteric; candida sepsis; candida granuloma; candidiasis oforal mucosa; vulvovaginal candidiasis;

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