Among the many different Candida species described in the literature, relatively few are common human pathogens and isolated from clinical specimens. In humans, Candida albicans has been recognized as the most common Candida species causing both colonization and infection. In general, the spectrums of disease caused by C. albicans and by non-C. albicans species have been similar. However, notable differences exist between C. albicans and pathogenic non-C. albicans species with respect to some important healthcare-associated epidemiologic associations, their prevalence in surveillance cultures, virulence potential, and innate resistance to antifungal drugs.

The only major natural reservoirs for Candida species microorganisms are humans and animals. Although there have been reports of healthcare-associated Candida species outbreaks in which the microorganism was isolated from hospital environmental sources, these are usually not implicated as causes of Candida species outbreaks. C. albicans is the most common Candida species to be implicated in healthcare-associated fungal infections. Other medically important Candida species include C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, C. lusitaniae, C. guillermondii, and C. dubliniensis. Since the 1980s, there has been a marked increase in bloodstream infections (BSIs) due to non-C. albicans Candida species, especially C. glabrata in the United States and C. parapsilosis and C. tropicalis in Europe, Canada, and Latin America coincident with the widespread implementation of azole drug prophylaxis and therapy. Because of the emergence of pathogenic non-C. albicans species that have variable resistance to antifungal drugs and their widely variable interinstitutional occurrence, the accurate identification of bloodstream and other invasive Candida isolates to species level has become an infection control priority. In addition, surveillance of antifungal susceptibility patterns for Candida species may be important as a component in an institution’s infection control program for these healthcare-associated fungal infections.

Candida species have been identified as saprophytes in the human respiratory tract, gastrointestinal tract, and vagina. Therefore, in the clinical laboratory, isolation of these microorganisms from specimens from these sites and the skin may be considered a normal finding. In addition, epidemiologic evidence suggests that in severely immunocompromised hospitalized patients, commensal yeast microorganisms are the major source of subsequent invasive infections. The pathogenesis of Candida species infections is multifactorial. Invasion by these colonizing Candida strains may be facilitated when there is disruption of local barriers, interference with the cellular host defenses, or both.

C. albicans appears to possess a number of virulence determinants, including proteases, adhesins, surface integrins, and switching, that may aid colonization at multiple sites and enable tissue invasion. Biofilm formation is a potential virulence factor that has been studied in vitro on catheter materials (23). It provides a protective niche from antifungal treatment for these microorganisms and thus may be the source of persistent infection (4). Relative to noninvasive Candida strains and species, invasive ones appear to be superior at forming biofilms, and unique biofilm morphology of C. albicans has been demonstrated compared to C. parapsilosis.

The intact skin is an effective barrier to invasion by Candida species. However, local disruption resulting from wounds (including intravascular catheters, burns, and ulceration) may permit skin penetration by these yeast microorganisms. Excessive moisture, as occurs in the perineum (in diapered infants), and hands and intertriginous regions (in workers whose hands are frequently immersed in water), may be another important local factor in determining sites of cutaneous or mucosal involvement.

Similarly, the intact gastrointestinal mucosa serves as a mechanical barrier preventing bloodstream invasion by Candida species. The passage of some Candida species microorganisms across the gastrointestinal tract wall may occur normally. However, disruption of this barrier, as occurs in patients with severe burns or those receiving cytotoxic chemotherapeutic drugs, may lead to Candida colonization and invasive infection.

Another locally protective mechanism in the gastrointestinal tract is the normal bacterial gut flora, which competes with colonizing Candida species microorganisms and prevents their overgrowth and subsequent bloodstream invasion. Antimicrobial agents that eliminate the gastrointestinal tract bacterial microflora and permit selective overgrowth of yeasts may be another cause of invasive disease in hospitalized patients.

The spectrum of host defenses against tissue invasion by Candida species include cell-mediated immunity that comprises cytokine release by lymphocytes and activation of natural killer cells and lymphocytes by interleukins. An increasing body of evidence also supports a role for specific antibody in protection against invasive Candida infection, which may have implications for potential vaccine development (24). Clinical observations indicate that mucocutaneous Candida infections are commonly associated with defective cell-mediated immune responses. Innate immunity is the dominant protective mechanism against disseminated candidiasis. Recognition of C. albicans by Toll-like receptors (TLRs) (mainly TLR2 and TLR4), on phagocytic cells activates intracellular signaling pathways that trigger production of proinflammatory cytokines that are critical for innate host defense and orchestrate the adaptive response (25). T helper (Th) cell reactivity plays a central role in regulating immune responses to C. albicans. Fungal infectivity is controlled by this proinflammatory (Th1) host response and optimized further through activation of Th2 and regulatory (Treg) cells. Recently, a new subset of Th cells, Th17, has been shown to play an important role in antifungal immunity (25). A mutation in the beta-glucan receptor dectin-1 important for development of Th-17 cells and related stimulation of cytokine production has also been found in women with recurrent vulvovaginal candidiasis or onychomycosis (26). Quantitative and qualitative abnormalities of neutrophils and monocytes are associated with invasive candidiasis.

The results of pathogenicity studies have suggested that C. parapsilosis and C. krusei isolates may be less virulent than those of other Candida species (C. albicans or C. tropicalis) (2,4,27,28). Other potentially important findings are the enhanced growth of C. parapsilosis isolates in solutions with high glucose concentration and an apparent selective growth advantage of the yeast in hyperalimentation solutions.

In severely immunocompromised patients, Candida infections usually have no specific symptoms and signs, and the only indication of underlying fungal infection may be fever that is unresponsive to antibacterial therapy. Nonetheless, clinical suspicion for the infection should be high in the management of predisposed severely ill patients. For patients predisposed to the infection, a careful search should be instituted for evidence of candidemia. For infected patients, establishing the diagnosis rapidly avoids an excessive and potentially life-threatening delay in instituting specific antifungal treatment.

The clinical presentation associated with candidemia may be variable. Some patients may have an acute onset of sepsis accompanied by high fever, chills, tachycardia, tachypnea, and hypotension with rapid progression to septic shock; alternatively, a chronic low-grade febrile illness may develop without any specific clinical findings. Development of septic shock in nonimmunocompromised patients with candidemia is rare, more often occurs in patients who have demonstrable renal failure, and is associated with a very high mortality (32). Importantly, patients with candidemia may progress to develop disseminated disease with eventual widespread involvement of multiple organs.

Cutaneous lesions may develop in patients with candidemia, especially those with acute leukemia. Although these lesions may be extremely variable in number and appearance, they are usually described as firm, erythematous, raised nodules. A definitive diagnosis is provided only by histopathologic examination of a skin biopsy specimen that demonstrates the presence of Candida species microorganisms in the dermis. Distinctive skin lesions also occur in premature neonates with congenital cutaneous candidiasis. This rare disorder results from prenatally acquired Candida species infection and is often associated with the presence of an intrauterine foreign body. The spectrum of involvement in these neonates ranges from diffuse skin eruption (macules, papules, and/or pustules that may evolve into vesicles and bullae) in the absence of systemic infection, which usually affects infants weighing more than 1,000 g, to widespread desquamating and/or erosive dermatitis predominately, which affects infants who weigh under 1,000 g and is associated with frequent development of invasive candidiasis and high mortality (33). In addition, candidemic patients frequently have evidence of muscle tenderness, particularly of the lower extremities. This may be the only clinical indication that the patient has an associated Candida myositis, and the diagnosis requires a muscle biopsy that shows histopathologic evidence of invasion of muscle tissue by Candida species.

Ocular candidiasis is common in patients with other clinical evidence of candidemia or invasive candidiasis. Ocular infection with Candida species is usually unilateral and often is asymptomatic. Patients with Candida species infection and ocular involvement demonstrate visual impairment, which may range from scotomata to complete blindness. Two prospective studies reported 9% and 26% candidemic patients, respectively, developed ocular candidiasis and emphasized the funduscopic finding of chorioretinitis (a focal white chorioretinal lesion with or without overlying vitreal haze) and less frequently the classic white fluffy mass with extension from the retina to the vitreous or a vitreal abscess (endophthalmitis) (34,35). It has been proposed that the less common occurrence of endophthalmitis in candidemic patients may result from more of these patients receiving prophylactic antifungal therapy. In a postmortem study by Edwards et al. (36), 22 of 26 patients (85%) had tissue candidiasis if hematogenous ocular candidiasis was present. Between 10% and 15% of surgical patients who were prospectively studied and received parenteral nutrition were found to demonstrate these same lesions (37). The diagnosis of Candida endophthalmitis usually relies on characteristic intraocular findings in a patient with risk factors for invasive candidiasis along with positive blood or vitreous fluid cultures (34). Krishna et al. (35) have recommended ophthalmologic follow-up for development of ocular candidiasis be done in patients for at least 2 weeks after an initial negative eye examination. The treatment of choice for this infection is usually systemic and intraocular amphotericin B therapy with or without flucytosine in conjunction with appropriate surgical management for advancing lesions or lesions threatening the macular (38); however, fluconazole is considered an acceptable alternative for less severe endophthalmitis (38). Among newer antifungal agents, voriconazole shows most promise, achieves high local and therapeutic concentrations in the vitreous against most Candida spp., when administered orally, and alternatively may be given as an intravitreal injection for sight-threatening macular involvement and vitritis. This agent may be useful for fluconazole-resistant, voriconazole-susceptible Candida strains (39). However, serum levels should be monitored because of high variability among patients (39). Posaconazole and the three echinocandins do not achieve adequate therapeutic levels in the vitreous (40). Removal of a lens implant, if present in the infected eye, is considered critical for the resolution of the infection (41). The outlook regarding the patient’s vision is usually guarded.

Dissemination of Candida infection to the central nervous system (CNS) as a result of hematogenous spread has been increasingly recognized and may often be accompanied by invasive Candida species infection at other sites. Characteristic involvement of the CNS by candidiasis may include meningitis, diffuse cerebritis with microabscesses, mycotic aneurysms, fungus ball formation, and parenchymal hemorrhage. In infected patients, the diagnostic usefulness of cerebrospinal fluid (CSF) examination may vary; involvement of specific anatomic CNS sites determines whether fungal microorganisms are in the CSF and the nature of the cellular content. Meningitis caused by Candida species has been most frequently reported to affect newborns (42). Intravenous amphotericin B with or without flucytosine is usually effective and intrathecal amphotericin B may be added to this regimen in some patients. Fluconazole is not recommended as primary therapy unless treatment with amphotericin B is contraindicated (38). Although the length of primary therapy has not been defined, several weeks of therapy are recommended before transition to treatment with an azole and only after the patient has demonstrated clinical and CSF improvement (38). Voriconazole may be appropriate therapy for C. glabrata or C. krusei meningitis after initial treatment with amphotericin B and flucytosine. Echinocandins are not recommended for CNS candidiasis. Removal of an infected ventricular device is recommended with systemic or systemic and intraventricular injection of amphotericin B into the device before its removal (38).

Chronic disseminated candidiasis (also called “hepatosplenic candidiasis”) is a form of localized invasive candidiasis that, as the name implies, most commonly involves the liver and/or spleen. As with other forms of invasive candidiasis, blood cultures are frequently negative in these patients, and the diagnosis may not be made until postmortem examination. The most common histopathologic findings are hepatic granulomas and microabscesses. This form of the disease predominantly affects severely granulocytopenic patients, in particular patients receiving chemotherapy with cytosine arabinoside for underlying acute myeloblastic leukemia. The disease usually coincides with recovery of the patient’s granulocyte count following a course of ablative chemotherapy. In these patients, gastrointestinal tract ulceration complicates receipt of this and other chemotherapeutic agents and allows gut-colonizing Candida species to gain direct access to the portal venous system. It has been suggested that this diagnosis should be suspected in any immunocompromised patient with unexplained fever with or without elevation of serum alkaline phosphatase or bilirubin. Magnetic resonance imaging is a technique that has also been shown to have high diagnostic accuracy for the acute, subacute-treated, and chronic-healed lesions of hepatosplenic fungal disease (43). Optimal antifungal therapy for the infection is considered to be amphotericin B for the acutely ill patient or when there is refractory disease (38). Fluconazole is recommended in clinically stable patients or step-down therapy following initial therapy with amphotericin B. Recently, however, the disease incidence has decreased dramatically at large leukemia and bone marrow transplant centers where fluconazole prophylaxis has been extensively used.

Endocarditis caused by Candida species often has been associated with disseminated infection in patients with malignancies. It can originate from intravenous catheters and affect high-risk infants, patients receiving parenteral nutrition, parenteral drug abusers, and cardiac surgical patients, particularly as a complication of prosthetic heart valve implantation (44). This infection may be an uncommon cause of persistent candidemia. However, only 50% of patients diagnosed postmortem with Candida endocarditis have positive premortem blood cultures for Candida species. Natural heart valves appear to be rarely affected; the infection usually is associated with implanted prosthetic heart valves. In their review of the Cleveland Clinic experience, Nasser et al. (45) found that patients with prosthetic heart valves who develop healthcare-associated candidemia are at significant risk of having or developing Candida prosthetic valve endocarditis even months or years later. These investigators also suggested that lateonset candidemia and lack of an identifiable portal of entry should heighten concern about Candida prosthetic valve endocarditis in such patients. Of 10 of their 11 patients with Candida prosthetic valve endocarditis treated with amphotericin B and valve replacement, 2 patients had a total of three documented relapses. Endocarditis may also occur as a secondary complication of an indwelling transvenous pacemaker, and surgical removal of the infected device and prolonged systemic antifungal therapy are required (46).

Suppurative peripheral thrombophlebitis caused by Candida species has been reported to be a distinct clinical entity that may uncommonly cause persistent candidemia. Walsh et al. (47) reported seven patients with this infection over a 15-month period. Factors implicated by these authors as important in the occurrence of these infections were catheter insertion techniques and suboptimal care of the catheter insertion site. Therapy usually comprises removal of the catheter, surgical intervention, and a short course of systemic antifungal therapy (38). Rarely, Candida species may infect arteriovenous dialysis fistulas, and effective treatment in these patients includes removal of the fistula and systemic antifungal therapy (48).

Peritonitis caused by Candida species has been reported as a complication in patients receiving long-term ambulatory peritoneal dialysis. Also, Candida species peritonitis may occur secondary to a perforated ulcer or postoperative anastomotic leakage following colonic surgery (as part of a polymicrobial infection) and may be complicated by the formation of intraperitoneal abscesses or subsequent candidemia. In patients with Candida species peritonitis, both an early diagnosis of the infection and prompt institution of specific systemic antifungal therapy are essential. In addition, appropriate surgical intervention in these patients to repair an underlying bowel perforation or to drain peritoneal abscesses may also be required.

Invasive renal candidiasis is most frequently the result of hematogenous dissemination and complicates candidemia or disseminated candidiasis. The kidney is the most commonly involved organ in invasive candidiasis (90%) (49). Rarely, usually only when there is coexistent obstruction, renal parenchymal infection and pyelonephritis are the result of retrograde renal tract infection.