Candida glabrata Antifungal Resistance and Virulence Factors, a Perfect Pathogenic Combination

Abstract

In recent years, a progressive increase in the incidence of invasive fungal infections (IFIs) caused by Candida glabrata has been observed. The objective of this literature review was to study the epidemiology, drug resistance, and virulence factors associated with the C. glabrata complex. For this purpose, a systematic review (January 2001–February 2021) was conducted on the PubMed, Scielo, and Cochrane search engines with the following terms: “C. glabrata complex (C. glabrata sensu stricto, C. nivariensis, C. bracarensis)” associated with “pathogenicity” or “epidemiology” or “antibiotics resistance” or “virulence factors” with language restrictions of English and Spanish. One hundred and ninety-nine articles were found during the search. Various mechanisms of drug resistance to azoles, polyenes, and echinocandins were found for the C. glabrata complex, depending on the geographical region. Among the mechanisms found are the overexpression of drug transporters, gene mutations that alter thermotolerance, the generation of hypervirulence due to increased adhesion factors, and modifications in vital enzymes that produce cell wall proteins that prevent the activity of drugs designed for its inhibition. In addition, it was observed that the C. glabrata complex has virulence factors such as the production of proteases, phospholipases, and hemolysins, and the formation of biofilms that allows the complex to evade the host immune response and generate fungal resistance. Because of this, the C. glabrata complex possesses a perfect pathogenetic combination for the invasion of the immunocompromised host.

Antifungal Resistance in Clinical Isolates of Candida glabrata in Ibero-America

“…A distinctive feature of C. glabrata is its low intrinsic susceptibility to fluconazole; however, the emergence of isolates with a true resistance to fluconazole has been constantly registered in recent years, leading to a greater use of echinocandins and other azoles, resulting in the emergence of isolates resistant to some of these types of antifungal agents; and thus, multidrug-resistant isolates have emerged [44,45]. Antifungal resistance in C. glabrata has been shown to vary with the geographic region [46], which highlights the importance of studying the antifungal susceptibility patterns at the local and regional levels.…”

How to Identify Invasive Candidemia in ICU—A Narrative Review

“…C. glabrata is the most commonly resistant identified species [ 12 ]. The reduced susceptibility to azoles has modified antifungal prescription practices for echinocandins; as a result, selection pressure increased resistance to echinocandins [ 23 , 24 , 25 ].…”

“…Accompanying the rise of invasive fungal infections, there is a worldwide rise of resistance of Candida to azoles and echinocandins [ 24 ]. The resistance to azoles has increased the use of echinocandins to treat Candida infections; as a consequence, exposure to echinocandins has led to reduced susceptibility [ 24 ]. The emergence of fungal resistance has an impact on patient outcomes.…”

Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata

“…C. glabrata infection incidences stand out as the second most common NAC in hospitals [ 23 ], and reports state that C. glabrata is intrinsically less susceptible to azole antifungal with a mortality rate of 50% in patients with invasive infections [ 24 , 25 , 26 ]. Several studies have been done to understand the resistance mechanism of C. glabrata among which increased drug efflux due to upregulation of efflux pump is the main described mechanism, which is caused by gain-of-function (GoF) mutation in CgPDR1, a transcriptional regulator of drug resistance [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Higher adherence and high number of adhesins which are encoded by EPA family genes is crucial for the pathogenicity of C. glabrata as well [ 37 ].…”