The incidence of fungal infections has increased significantly, so contributing to morbidity and mortality. This is caused by an increase in antimicrobial resistance and the restricted number of antifungal drugs, which retain many side effects. Candida species are major human fungal pathogens that cause both mucosal and deep tissue infections. Recent evidence suggests that the majority of infections produced by this pathogen are associated with biofilm growth. Biofilms are biological communities with a high degree of organization, in which micro-organisms form structured, coordinated and functional communities. These biological communities are embedded in a self-created extracellular matrix. Biofilm production is also associated with a high level of antimicrobial resistance of the associated organisms. The ability of Candida species to form drug-resistant biofilms is an important factor in their contribution to human disease. The study of plants as an alternative to other forms of drug discovery has attracted great attention because, according to the World Health Organization, these would be the best sources for obtaining a wide variety of drugs and could benefit a large population. Furthermore, silver nanoparticles, antibodies and photodynamic inactivation have also been used with good results. This article presents a brief review of the literature regarding the epidemiology of Candida species, as well as their pathogenicity and ability to form biofilms, the antifungal activity of natural products and other therapeutic options.

Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options

The incidence of infections caused by Candida species (candidosis) has increased considerably over the past three decades, mainly due to the rise of the AIDS epidemic, an increasingly aged population, higher numbers of immunocompromised patients and the more widespread use of indwelling medical devices. Candida albicans is the main cause of candidosis; however, non-C. albicans Candida (NCAC) species such as Candida glabrata, Candida tropicalis and Candida parapsilosis are now frequently identified as human pathogens. The apparent increased emergence of these species as human pathogens can be attributed to improved identification methods and also associated with the degree of diseases of the patients, the interventions that they were subjected and the drugs used. Candida pathogenicity is facilitated by a number of virulence factors, most importantly adherence to host surfaces including medical devices, biofilm formation and secretion of hydrolytic enzymes (e.g. proteases, phospholipases and haemolysins). Furthermore, despite extensive research to identify pathogenic factors in fungi, particularly in C. albicans, relatively little is known about NCAC species. This review provides information on the current state of knowledge on the biology, identification, epidemiology, pathogenicity and antifungal resistance of C. glabrata, C. parapsilosis and C. tropicalis.

Candida glabrata, Candida parapsilosis and Candida tropicalis: biology, epidemiology, pathogenicity and antifungal resistance

Summary: Candida parapsilosis is an emerging major human pathogen that has dramatically increased in significance and prevalence over the past 2 decades, such that C. parapsilosis is now one of the leading causes of invasive candidal disease. Individuals at the highest risk for severe infection include neonates and patients in intensive care units. C. parapsilosis infections are especially associated with hyperalimentation solutions, prosthetic devices, and indwelling catheters, as well as the nosocomial spread of disease through the hands of health care workers. Factors involved in disease pathogenesis include the secretion of hydrolytic enzymes, adhesion to prosthetics, and biofilm formation. New molecular genetic tools are providing additional and much-needed information regarding C. parapsilosis virulence. The emerging information will provide a deeper understanding of C. parapsilosis pathogenesis and facilitate the development of new therapeutic approaches for treating C. parapsilosis infections.

Candida parapsilosis, an Emerging Fungal Pathogen

Relative frequency of albicans and the various non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a systematic review.

Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced Vmax values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.

Background Studies conducted in tertiary care hospitals of different European countries and the United States have shown incidence rates of candidemia ranging from 0.17 to 0.76 and 0.28 to 0.96 per 1,000 admissions, respectively. So far, only 1 study has evaluated the incidence rates of candidemia in tertiary care hospitals in Latin American countries. Objective To evaluate the epidemiology of candidemia in 4 tertiary care hospitals in Sao Paulo, Brazil. Design Multicenter, laboratory-based surveillance of candidemia. Results A total of 7,038 episodes of bloodstream infection were identified, and Candida species accounted for 282 cases (4%). The incidence rate of candidemia was 1.66 candidemic episodes per 1,000 hospital admissions. Candida albicans was the most frequently isolated Candida species in all hospitals, but Candida species other than C. albicans accounted for 62% of isolates, including predominantly Candida parapsilosis and Candida tropicalis. Azole resistance was restricted to only 2% of all Candida isolates (1 isolate of Candida glabrata and 4 isolates of Candida rugosa). Candidemia was mostly documented in surgical patients with long durations of hospital stay. The crude mortality rate was 61%, and advanced age and high Acute Physiology and Chronic Health Evaluation II score were both conditions independently associated with risk of death. Conclusions We observed in our series a higher incidence rate of candidemia than that reported in European countries and the United States. Advanced age and a high Acute Physiology and Chronic Health Evaluation II score were factors associated with a higher probability of death in candidemic patients. Fluconazole-resistant Candida strains are still a rare finding in our case-based study of candidemia.

Patrícia Rady

Papers

Prospective observational study of candidemia in São Paulo, Brazil: incidence rate, epidemiology, and predictors of mortality.