Evaluation of Molecular Epidemiology, Clinical Characteristics, Antifungal Susceptibility Profiles, and Molecular Mechanisms of Antifungal Resistance of Iranian Candida parapsilosis Species Complex Blood Isolates

Abstract

Clonal expansion of fluconazole resistant (FLZ-R) Candida parapsilosis isolates is increasingly being identified in many countries, while there is no study exploring the antifungal susceptibility pattern, genetic diversity, and clinical information for Iranian C. parapsilosis blood isolates. Candida parapsilosis species complex blood isolates (n = 98) were recovered from nine hospitals located in three major cities, identified by MALDI-TOF MS, and their genetic relatedness was examined by AFLP fingerprinting. Antifungal susceptibility testing followed CLSI-M27-A3 and ERG11, MRR1 and hotspots 1/2 (HS1/2) of FKS1 were sequenced to assess the azole and echinocandin resistance mechanisms, respectively. Ninety-four C. parapsilosis and four Candida orthopsilosis isolates were identified from 90 patients. Only 43 patients received systemic antifungal drugs with fluconazole as the main antifungal used. The overall mortality rate was 46.6% (42/90) and death mostly occurred for those receiving systemic antifungals (25/43) relative to those not treated (17/47). Although, antifungal-resistance was rare, one isolate was multidrug-resistant (FLZ = 16 µg/ml and micafungin = 8 µg/ml) and the Arastehfar et al. Candida parapsilosis Blood Isolates Typing infected patient showed therapeutic failure to FLZ prophylaxis. Mutations causing azole and echinocandin resistance were not found in the genes studied. AFLP revealed five genotypes (G) and G1 was the main one (59/94; 62.7%). Clinical outcome was significantly associated with city (P = 0.02, α <0.05) and Mashhad was significantly associated with mortality (P = 0.03, α <0.05). Overall, we found a low level of antifungal resistance for Iranian C. parapsilosis blood isolates, but the noted MDR strain can potentially become the source of future infections and challenge the antifungal therapy in antifungal-naïve patients. AFLP typing results warrants confirmation using other resolutive typing methods.

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

“…Generally, changes in drug affinity at the drug target for azoles and echinocandins and overexpression of the drug target and efflux pumps are the major determinants of azole resistance. Considering that azoles are the main drug used to treat invasive candidiasis in developing countries [ 63 , 91 , 121 , 122 , 123 ], having a clear understanding of resistance mechanisms is of paramount importance ( Figure 2 ). Although modification of the drug target, ERG11 , is an important azole resistance mechanism in species belonging to CTG ( C .…”

“…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 .…”

The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

“…The high rate of FLZR for a species that used to be susceptible to azoles may have arisen from the disproportionate use of azoles in the hospital [170,182]. The notable increase in the prevalence of FLZR C. parapsilosis isolates could be a major threat in developing countries, in which the vast majority of candidemia cases are treated with FLZ [138,169,182,186]. By contrast, according to the SENTRY study, echinocandin resistance is a rare phenomenon among C. parapsilosis isolates (up to 0.1%) [79].…”

“…The notable increase in the prevalence of FLZR C . parapsilosis isolates could be a major threat in developing countries, in which the vast majority of candidemia cases are treated with FLZ [ 138 , 169 , 182 , 186 ]. By contrast, according to the SENTRY study, echinocandin resistance is a rare phenomenon among C .…”

Efficacy of LAMB against Emerging Azole- and Multidrug-Resistant Candida parapsilosis Isolates in the Galleria mellonella Model

“…Surprisingly, new studies from Turkey [ 17 , 18 ] and South Korea [ 20 ] reported a substantial increase in prevalence of FLCR C. parapsilosis after 2015, which appeared partially due to the expanded use of azoles in clinical settings. Despite extremely low rates of echinocandin-resistant C. parapsilosis blood isolates [ 1 ], recent candidemia studies from Iran [ 21 ] and Turkey [ 22 ] have shown emerging multidrug-resistant (MDR) C. parapsilosis isolates resistant against both echinocandins and azoles. Of particular concern is the horizontal transfer of clonal FLCR and MDR C. parapsilosis to antifungal-naïve patients [ 18 , 22 ], which notoriously limit the efficacy of these two most widely used antifungals.…”