The genus Candida consists of yeasts that commonly live harmlessly on human skin and mucosal surfaces, but they can cause serious infections under certain conditions. While Candida albicans remains the most frequently isolated species, non-albicans species, particularly Candida glabrata and Candida krusei, are a growing concern in clinical settings. These two species are significant because they display inherent or rapidly acquired resistance to common antifungal medications. This resistance complicates treatment and contributes to high mortality rates in hospitalized patients, representing a serious challenge to effective patient care.
Biological Characteristics and Risk Factors
C. glabrata and C. krusei differ biologically from C. albicans, influencing their virulence and behavior in the host. Unlike C. albicans, which is dimorphic and can switch between yeast and filamentous forms, C. glabrata is found almost exclusively in the yeast form (blastoconidia). Although this morphology suggests lower virulence, C. glabrata is associated with a high mortality rate in compromised patients.
C. krusei also has distinct biological traits and is generally grouped with other non-albicans species. The increased frequency of infections caused by these two yeasts is closely linked to specific patient vulnerabilities and medical interventions. Patients with neutropenia, chronic renal disease, underlying malignancies, or those who have undergone solid organ transplantation are at increased risk.
A primary predisposing factor for infection by these resistant species is prior exposure to azole antifungal drugs, such as fluconazole, which selects for naturally less susceptible organisms. Other common risk factors include prolonged hospitalization, admission to an intensive care unit, advanced age, and the presence of indwelling medical devices like central venous catheters.
Sites of Infection
Infections caused by C. glabrata and C. krusei tend to manifest in severe, systemic forms, distinguishing them from the superficial infections typically caused by C. albicans. Both species are major causes of candidemia, a bloodstream infection that carries a significant risk of death. Candidemia is often the precursor to invasive candidiasis, where the infection spreads to deep organs.
Systemic infections frequently involve the urinary tract, making C. glabrata a common cause of fungal urinary tract infections. These species are also implicated in deep-seated infections, particularly those occurring in the abdomen, such as peritonitis and intra-abdominal abscesses, often following major surgery.
Mechanisms of Antifungal Drug Resistance
The primary concern with C. glabrata and C. krusei is their capacity for antifungal drug resistance, stemming from distinct biological mechanisms. C. krusei possesses intrinsic resistance to fluconazole and other first-generation azoles. This inherent resistance is primarily due to a structural alteration in the fungal target enzyme, \(14\alpha\)-demethylase (encoded by the CYP51 gene). The modified \(14\alpha\)-demethylase in C. krusei has a reduced affinity for fluconazole, making the drug less effective at inhibiting the enzyme compared to its activity in C. albicans isolates.
C. glabrata frequently exhibits acquired or dose-dependent resistance to azoles. The main mechanism involves the overexpression of drug efflux pumps, specifically those encoded by the CDR1 and CDR2 genes, which belong to the ATP-binding cassette family of transporters. These pumps actively remove the azole drug from the fungal cell, preventing it from reaching its target. The upregulation of these efflux pumps is commonly regulated by gain-of-function mutations in the PDR1 transcriptional factor.
C. glabrata is also concerning due to its potential for reduced susceptibility to echinocandins, a different class of antifungal medication. Resistance to echinocandins arises from point mutations in the FKS1 and FKS2 genes, which encode subunits of the \(\beta\)-1,3-glucan synthase enzyme. These mutations change the shape of the target site, preventing the echinocandin drug from binding effectively and leading to treatment failure.
Therapeutic Strategies
Given the high rates of azole resistance, current guidelines recommend a shift away from fluconazole for the initial treatment of infections caused by C. glabrata and C. krusei. The echinocandin class of antifungals, which includes caspofungin, micafungin, and anidulafungin, is generally considered the first-line therapy for severe or invasive infections with these species. Echinocandins work differently from azoles by targeting the fungal cell wall, which is a mechanism that remains effective against most azole-resistant strains.
For cases where the organism is resistant to echinocandins or for particularly severe infections, Amphotericin B formulations are often employed as alternative or salvage therapy. Voriconazole, a newer-generation azole, may also be considered for C. krusei infections because it retains greater activity against this species than fluconazole, although its use is often guided by specific susceptibility testing results. Antifungal susceptibility testing (AST) is an important tool in the management of these infections, as it helps clinicians select an effective agent based on the specific resistance profile of the isolated strain.
A non-pharmacological but equally important aspect of management is source control, which involves the removal of any infected foreign material, such as central venous catheters. The removal of these devices is strongly recommended in cases of candidemia, as they often serve as a persistent source of infection and a surface for biofilm formation that shields the yeast from antifungal drugs. Combining effective systemic antifungal therapy with aggressive source control is paramount for improving patient outcomes.