Candida dubliniensis is a yeast species closely related to the more common Candida albicans, first identified in the mid-1990s. This opportunistic fungus has garnered attention due to its frequent isolation from immunocompromised patients worldwide. The organism’s response to antifungal medications is a primary concern, particularly its propensity to develop resistance during prolonged treatment. This analysis focuses on the intrinsic drug susceptibility of C. dubliniensis and the adaptive strategies it employs to evade common antifungal therapies.
Taxonomy and Clinical Significance
Candida dubliniensis is a distinct species closely related to C. albicans, sharing a remarkably close genetic and phenotypic relationship. Both species form characteristic structures like germ tubes and chlamydospores, which historically led to the misidentification of C. dubliniensis isolates as “atypical” C. albicans strains. A key laboratory difference is that most C. dubliniensis strains exhibit poor or no growth when cultured at 42°C, unlike C. albicans.
The yeast is an opportunistic pathogen, predominantly causing oral candidiasis in immunocompromised individuals. It was originally isolated from patients with Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS), where it is frequently found in the oral cavity. Although less virulent than C. albicans, C. dubliniensis has a worldwide distribution and has been isolated from various other sites, including the respiratory tract, urine, and blood, leading to candidemia.
Accurate identification is important for patient management due to the organism’s unique susceptibility profile and its tendency to acquire drug resistance quickly. Modern molecular techniques or differential media are often necessary to reliably distinguish it from its close relative. C. dubliniensis is recognized as a pathogen of concern, particularly in individuals with underlying immune deficits.
Baseline Antifungal Susceptibility
The intrinsic susceptibility of C. dubliniensis to antifungal agents is generally favorable before exposure to prolonged therapy. Initial clinical isolates are often sensitive to the three major classes of antifungals, allowing for effective initial treatment.
The Azole class, such as Fluconazole, is commonly used for mucosal infections. Most non-resistant isolates show susceptibility to Fluconazole and other Azoles like Voriconazole. However, susceptibility to Fluconazole is often slightly lower than that of C. albicans, and some initial clinical isolates already exhibit reduced susceptibility or resistance.
The Echinocandin class, including agents like Caspofungin, is highly effective against C. dubliniensis isolates. Echinocandins target the fungal cell wall and are considered a reliable option for treating severe or systemic Candida infections. Their high efficacy makes them an important alternative when Fluconazole resistance is suspected or confirmed.
Polyene antifungals, primarily Amphotericin B, are also highly active against C. dubliniensis. This drug class works by binding to ergosterol in the fungal cell membrane, leading to cell death. Although potent, Amphotericin B is typically reserved for life-threatening or deeply invasive infections due to its potential for toxicity. The ease with which C. dubliniensis can develop resistance to Azoles remains a significant clinical challenge.
Adaptive Resistance Mechanisms
The most concerning characteristic of C. dubliniensis is its ability to rapidly develop stable, acquired resistance, particularly to Azole drugs like Fluconazole, often following prolonged exposure in a host. This mirrors the clinical problem seen in patients undergoing long-term antifungal therapy.
One primary mechanism of acquired Azole resistance is the overexpression of specific drug efflux pumps located in the cell membrane. C. dubliniensis increases the production of transporters from the ATP-binding cassette (ABC) and Major Facilitator Superfamily (MFS) families, such as CDR1 and MDR1. These pumps actively export the antifungal drug out of the fungal cell, reducing the intracellular concentration to a non-inhibitory level.
Alterations in the drug target itself also contribute to adaptive resistance. Azole drugs inhibit the enzyme lanosterol 14-alpha-demethylase, which is encoded by the ERG11 gene and is necessary for ergosterol synthesis. The fungus can develop mutations in the ERG11 gene, which change the shape of the target enzyme, thereby lowering the drug’s binding affinity. Furthermore, the organism may increase the expression of the ERG11 gene, producing more target enzyme, which effectively saturates the available drug and allows some ergosterol synthesis to continue.
The capacity of C. dubliniensis to form robust biofilms is a non-molecular mechanism that provides a physical shield against antifungals and host immune cells. Cells within this extracellular matrix, known as sessile cells, exhibit increased resistance to Fluconazole and, to a lesser extent, Amphotericin B, compared to free-floating planktonic cells.
The extracellular matrix within the biofilm physically sequesters the antifungal drug, preventing it from reaching deeper cell layers. Furthermore, cells often exist in a state of slow growth or metabolic dormancy, sometimes called “persister cells,” which are inherently less susceptible to antimicrobial agents. This combination of physical protection and metabolic changes explains the challenge in eradicating C. dubliniensis infections.