IC is not associated with any specific symptoms. Patients may present with fever, and do not show a favorable response to broad-spectrum antibiotics. Otherwise, symptoms depend on the site of tissue invasion and may correspond to those observed in individuals suffering from:

• Chorioretinitis and endophthalmitis
• Endocarditis
• Meningitis
• Osteomyelitis and spondylodiscitis
• Arthritis or prosthetic joint infection
• Peritonitis

Anamnestic data are of major importance to identify patients at risk of IC, since clinical findings are generally non-specific. Furthermore, symptoms triggered by disseminated candidiasis may be masked by those related to comorbidities. Blood samples should be obtained from patients who are suspected to have IC and be sent for blood cultures. Although this approach is considered the gold standard for diagnosis, it yields negative results in case of non-candidemic systemic candidiasis and lacks sensitivity for candidemia. With regards to the latter, molecular biological techniques and immunoassays have increasingly been applied to demonstrate the presence of Candida spp. in blood specimens [8]. Immunoassays are employed to prove the presence of components of the fungal cell wall, namely of mannan and (1–3)-β-D-glucan. Conduction of multiple tests may be required to augment both specificity and sensitivity of the diagnostic workup.

Confirmation of non-candidemic, deep-seated candidiasis is a major challenge. Essentially, available techniques correspond to those described before, i.e., they comprise tissue cultures and detection of Candida antigens by polymerase chain reaction or immunoassays. Neither test yields reliable results with regards to specificity and sensitivity. Moreover, in order to examine tissue cultures, invasive procedures have to be carried out. Histopathologic evidence of invasion is required to distinguish IC from mere colonization with Candida spp. In this line, the presence of blastospores, hyphae or pseudohyphae has to be demonstrated. Diagnostic imaging (e.g., endoscopy, endocardiography) is recommended to assess the involvement of additional organs.

The administration of echinocandins like anidulafungin, caspofungin or micafungin is highly recommended for the initial treatment of IC [9] [10]. Dosage is as follows:

• Anidulafungin: an initial dose of 200 mg followed by daily doses of 100 mg
• Caspofungin: an initial dose of 70 mg followed by daily doses of 50 mg
• Micafungin: daily doses of 100 mg

Most experts also support the use of liposomal amphotericin B (3 mg/kg per day), voriconazole (initially 6 mg/kg per day, subsequently reduction to 3 mg/kg per day) and fluconazole (an initial dose of 12 mg/kg followed by daily doses of 6 mg/kg) in affected individuals. Evidence regarding the efficacy of distinct formulations of amphotericin B and other azoles is at best of moderate quality. Ideally, the final decision on the appropriate antifungal treatment is based on the results of susceptibility testing. In case of candidemia, antimycotic therapy should be continued for a minimum of two weeks after daily blood cultures yield negative results and after resolution of neutropenia and candidemia-related symptoms.

Sole systemic drug therapy is often insufficient to treat deep-seated candidiasis. For instance, intravitreal injection of antimycotic drugs and vitrectomy should be considered in patients with ocular IC. Patients diagnosed with candidal endocarditis should undergo surgery within a few days.

Indwelling catheters and infected prostheses should be removed if at all possible.

IC is still related to mortality rates of 35 to 60% [4]. This is due to the fact that the disease is not usually diagnosed until advanced stages, and this particularly applies to cases not associated with candidemia. Furthermore, drug resistance is a major problem, especially in case of infection with C. glabrata, C. parapsilosis, or C. krusei. Prevalence rates of those species are higher among patients who previously received antifungal therapy. C. parapsilosis is able to form biofilms which render the fungus even more resistant to eradication. Because prolonged hospitalization increases the overall risk of infection, the duration of hospital stay may also be considered an unfavorable prognostic factor.

The etiologic agents of IC are opportunistic pathogens pertaining to a genus of yeast named Candida. Candida spp. are ubiquitously present in the environment and in the microflora of the human body. They are best known for causing cutaneous and vaginal candidiasis (commonly referred to as thrush and vaginal mycosis). Contrary to those entities, IC is associated with an infiltration of usually sterile sites by Candida spp. In sum, more than a dozen Candida spp. have been associated with IC.

The following species are frequently isolated from IC lesions [2]:

• C. albicans
• C. glabrata
• C. parapsilosis
• C. tropicalis
• C. krusei

Fewer case reports exist on IC due to infections with [3]:

• C. lusitaniae
• C. guilliermondii
• C. dubliniensis
• C. kefyr
• C. pelliculosa
• C. famata
• C. rugosa
• C. lipolytica
• C. zeylanoides
• C. inconspicua
• C. lambica
• C. sake

This list is expected to grow as species identification gains importance in IC workup.

While a colonization of skin and mucous membranes is observed in large proportion of severely ill, hospitalized patients, IC is less common [4]. The latter is most frequently diagnosed in patients hospitalized in intensive care units, in those who recently underwent surgery, those who suffer from solid tumors, hematological malignancies, or immunodeficiency due to an infection with human immunodeficiency virus (HIV). Furthermore, transplant patients and those who have a central venous catheter are at higher risks of developing IC. Accordingly, demographic data of IC patients largely reflect the epidemiology of the aforementioned diseases: French researchers have worked with more than 2,400 blood samples obtained from patients with candidemia, the vast majority of whom were adults [2]. Their mean age was 59 years, but specimens have been collected from patients as young as 15 years and as old as 99 years. Males accounted for approximately 60% of pediatric and adult patients. In the United States, overall IC incidence rates of up to 29 per 100,000 inhabitants and 24 per 10,000 hospital discharges have been reported [5]. Similar incidence rates are to be expected elsewhere as no significant geographical differences in the prevalence of Candida infections in patients hospitalized in intensive care units have been demonstrated [6].

The source of pathogens triggering IC has been a matter of intense debate. Candida spp. may colonize human skin and the intestinal tract, and this condition is not typically associated with clinical symptoms. IC develops when fungi spread to other tissues, either from exogenous or endogenous sites. While both routes of infection presumably play a role in IC pathogenesis, available data imply the latter to be more common [7]. However, inoculation of fungi originating from the skin is assumed to account for catheter-related IC. In general, the risk of IC correlates with the prevalence of Candida spp. in either site. Patients hospitalized in intensive care units are generally treated with broad-spectrum antibiotics that may induce changes in species composition of their skin and gut flora, and this may favor Candida overgrowth.

Only upon destruction of the physical integrity of the cutaneous or intestinal mucosal barrier, or in case of functional deficits, can Candida. spp. reach the bloodstream and internal organs. In this context, surgery, especially gastrointestinal surgery, largely facilitates the spread of pathogens. Neutrophil granulocytes are part of the innate immune system and fulfill important functions in controlling yeast infections. But those who are immunodeficient either due to immunosuppressive therapy (to avoid transplant rejection) or due to hematological malignancies or HIV infection , are often neutropenic. Also, lesions of mucous membranes are common in patients receiving cytostatic drugs for cancer.

While the prophylactic use of antifungal compounds may hinder the spread of pathogens colonizing the patient's skin and mucous membranes, it increases the risk of resistance development and increases the prevalence of less susceptible Candida spp. This has been observed in a recent study conducted in France: antimycotic treatment was shown to decrease the prevalence of C. albicans, but at the same time, prevalence rates of C. glabrata, C. parapsilosis and C. krusei increased [2]. Thus, antimycotic prophylaxis should only be given to selected patients, and guidelines have been established to aid the decision on whether a critically ill or immunodeficient patient requires such medication [9] [11]. Briefly, these guidelines consider antifungal prophylaxis for the following patient groups:

• Extremely low-birth weight neonates.
• Severely neutropenic patients who present with fever refractory to broad-spectrum antibiotic treatment.
• Those who recently underwent abdominal surgery and suffer from recurrent gastrointestinal perforations or anastomotic leakages.
• Critically ill patients who recently underwent surgery and who are expected to remain hospitalized in intensive care units for more than three days.
• Patients who are expected to be ventilated for a total of more than five days.

The interested reader is referred to the cited studies, which include more detailed information including the drugs of choice and their dosage.

Alternatively, high-risk patients may be identified by serological markers and score systems [4] [12].

The term invasive candidiasis (IC) describes an infection of physiologically sterile sites of the human body with fungi belonging to the genus Candida. If these pathogens spread hematogenously from the primary site of colonization, patients develop candidemia, which is considered the most common form of IC. Furthermore, IC may refer to non-candidemic systemic candidiasis, and this condition is associated with growth and reproduction of fungi in the abdomen, heart, central nervous system, joints, bones, eyes, and other tissues [1].

IC is primarily a nosocomial infection. Because Candida spp. may colonize the skin and intestinal mucous membranes of humans, any pathology or procedure interfering with the physical or functional integrity of the respective barriers may predispose for Candida dissemination. This mainly concerns critically ill and immunocompromised patients. IC is not associated with any specific symptoms, and although the isolation and identification of Candida spp. in blood and tissue cultures is considered the gold standard for IC diagnosis, these procedures lack sensitivity. Thus, confirmation of IC remains a major challenge. In this context, the identification of risk factors predisposing for IC is of utmost importance to prevent diagnostic delays and to initiate the appropriate treatment as early as possible. Still, about half of IC patients succumb to the disease.

Candidiasis refers to an infection with yeast pertaining to the genus Candida. These opportunistic pathogens are best known for causing thrush and vaginal mycosis, but in these entities, fungi do not invade the bloodstream and do not spread to internal organs. In contrast, invasive candidiasis (IC) describes an infection of physiologically sterile sites of the human body.

Candida species may colonize human skin and the intestinal tract, and this condition is not typically associated with clinical symptoms. However, if the physical and functional integrity of the cutaneous or intestinal mucosal barrier is disturbed, fungi may spread to the bloodstream, to the abdominal cavity, and eventually to the eyes, heart, joints, bones, and central nervous system. Most frequently, this occurs in individuals who recently underwent abdominal surgery, who suffer from solid tumors, lymphoma or leukemia, whose immune system is compromised due to an infection with human immunodeficiency virus or immunosuppressive therapy. Additional known risk factors are prolonged hospitalization in intensive care units and ventilation.

Treatment mainly consists of systemic administration of antimycotic drugs like anidulafungin, caspofungin, amphotericin B or fluconazole. Medication is initially given intravenously, but patients are later given drugs that can be ingested orally. In case the eyes, the heart, or skeleton are affected, patients may need to undergo surgery. Unfortunately and despite provision of optimum therapy, about half of IC patients succumb to the disease. Because of the detrimental consequences of IC, high-risk patients are administered antifungal prophylaxis.

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