Recent Increase in the Prevalence of Fluconazole-Non-susceptible Candida tropicalis Blood Isolates in Turkey: Clinical Implication of Azole-Non-susceptible and Fluconazole Tolerant Phenotypes and Genotyping

Abstract

Candida tropicalis is the fourth leading cause of candidemia in Turkey. Although C. tropicalis isolates from 1997 to 2017 were characterized as fully susceptible to antifungals, the increasing global prevalence of azole-non-susceptible (ANS) C. tropicalis and the association between high fluconazole tolerance (HFT) and fluconazole therapeutic failure (FTF) prompted us to re-evaluate azole susceptibility of C. tropicalis in Turkey. In this study, 161 C. tropicalis blood isolates from seven clinical centers were identified by ITS rDNA sequencing, genotyped by multilocus microsatellite typing, and tested for susceptibility to five azoles, two echinocandins, and amphotericin B (AMB); antifungal resistance mechanisms were assessed by sequencing of ERG11 and FKS1 genes. The results indicated that C. tropicalis isolates, which belonged to 125 genotypes grouped into 11 clusters, were fully susceptible to echinocandins and AMB; however, 18.6% of them had the ANS phenotype but only two carried the ANS-conferring mutation (Y132F). HFT was recorded in 52 isolates, 10 of which were also ANS. Large proportions of patients infected with ANS and HFT isolates (89 and 40.7%, respectively) showed FTF. Patients infected with azole-susceptible or ANS isolates did not differ in mortality, which, however, was significantly lower for those infected with HFT isolates ( P = 0.007). There were significant differences in mortality ( P = 0.02), ANS ( P = 0.012), and HFT ( P = 0.007) among genotype clusters. The alarming increase in the prevalence of C. tropicalis blood isolates with ANS and HFT in Turkey and the notable FTF rate should be a matter of public health concern.

COVID-19-Associated Candidiasis (CAC): An Underestimated Complication in the Absence of Immunological Predispositions?

“…Persistent invasive yeast infections have been noted during the course of antifungal therapy, while the yeasts isolated showed susceptible profiles to the antifungal used for treatment [ 25 , 27 ]. Most notably, 67% of the patients who died with invasive yeast infections due to C. auris showed persistent candidemia, despite being treated with micafungin [ 27 ] in the absence of resistance, which might be explained by other host and pathogen-related factors [ 44 , 45 , 46 ]. Therefore, these data highlight the urgency of conducting comprehensive studies elucidating the real burden of each entity among COVID-19 cases manifesting ARDS.…”

Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium

“…Recently, it was observed that almost 35% of C . tropicalis blood isolates showed a high-level of fluconazole tolerance (≥ 50% of drug-free control), among which almost one-third of infected patients showed therapeutic failure when treated with fluconazole [ 118 ]. Moreover, significant variation in tolerance observed among clinical isolates has been associated with a difference in genetic backgrounds [ 119 ], which may reflect the mutagenesis potential of a given isolate to induce resistance [ 22 ].…”

“…Indeed, it was found that some microsatellite clusters contained a significantly higher number of high fluconazole-tolerant C . tropicalis isolates and vice versa [ 118 ]. Unfortunately, despite that there is extensive knowledge about antibiotic tolerance in clinically important bacterial species, our current understanding of antifungal tolerance is still in its infancy.…”

“…Unfortunately, despite that there is extensive knowledge about antibiotic tolerance in clinically important bacterial species, our current understanding of antifungal tolerance is still in its infancy. These studies emphasize the clinical significance of antifungal tolerance, and it is recommended to consider the level of tolerance observed (≥50–75% of drug-free control) when choosing an antifungal agent in the clinic [ 116 , 118 ]. It is noteworthy that the existing inhibitory compounds used against stress pathways employed by human fungal pathogens are already used in the clinic and have a profound impact on the host by impairing immune functions [ 112 , 120 ].…”

“…tropicalis and C . parapsilosis isolates [ 47 , 118 , 122 , 134 , 135 , 136 ], which could serve as a basis to broaden our understanding of azole resistance mechanisms in C . parapsilosis and C .…”