Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy

Abstract

Candida lusitaniae is usually susceptible to echinocandins. Beta-1,3-glucan synthase encoded by FKS genes is the target of echinocandins. A few missense mutations in the C. lusitaniae FKS1 hot spot 1 (HS1) have been reported. We report here the rapid emergence of antifungal resistance in C. lusitaniae isolated during therapy with amphotericin B (AMB), caspofungin (CAS), and azoles for treatment of persistent candidemia in an immunocompromised child with severe enterocolitis and visceral adenoviral disease. As documented from restriction fragment length polymorphism (RFLP) and random amplified polymorphic DNA (RAPD) analysis, the five C. lusitaniae isolates examined were related to each other. From antifungal susceptibility and molecular analyses, 5 different profiles (P) were obtained. These profiles included the following: profile 1 (P1) (CAS MIC . While S638Y and -P are within HS1, S631Y is in close proximity to this domain but was confirmed to confer candin resistance using a site-directed mutagenesis approach. FLC resistance could be linked with overexpression of major facilitator gene 7 (MFS7) in C. lusitaniae P2 and P4 and was associated with resistance to 5-flurocytosine. This clinical report describes resistance of C. lusitaniae to all common antifungals. While candins or azole resistance followed monotherapy, multidrug antifungal resistance emerged during combined therapy.[ Candida lusitaniae, an opportunistic haploid yeast, remains a rare cause of candidemia. While C. lusitaniae can develop amphotericin B (AMB) resistance (1, 2), it is considered generally susceptible to all systemic antifungal agents (3). Echinocandins are used as first-line therapy for candidemia due to C. lusitaniae. The target of echinocandins is ␤-1,3-glucan synthase and is encoded by FKS genes (4). Three echinocandins, anidulafungin (ANI), caspofungin (CAS), and micafungin (MICA), have been available and widely used for about a decade. As a result, emerging resistance to echinocandins has been reported in several species, including C. albicans, C. dubliniensis, C. kefyr, C. glabrata, C. krusei, C. tropicalis, and C. lusitaniae (5-12). Missense mutations in FKS genes (FKS1 and FKS2) that are situated in different regions (host spot 1 [HS1] and HS2) are responsible for the increase of drug MICs compared to the MICs seen with wild-type isolates. These MIC increases were shown to cause treatment failures in animal experiments similarly to those seen in clinical cases, thus suggesting the emergence of clinical resistance (13). In C. lusitaniae, a single missense mutation in C. lusitaniae FKS1 HS1 at position 645 (S645F) was reported in clinical isolates and resulted in increased MICs of several echinocandins. While recent data documented cross-resistance between echinocandins and azoles in C. glabrata (14), no cross-resistance has yet been reported in C. lusitaniae. The present paper reports the unusual emergence of clinical isolates of C. lusitaniae with documented cross-resistance to candins and azoles following exposure to various ...

Emerging Threats in Antifungal-Resistant Fungal Pathogens

“…FKS1 mutations have been reported in these two regions (HS1: region 640–650 and HS2: 1345–1365) in clinical isolates of C. albicans ( 70 ). Equivalent mutations in the HS1 of FKS2 (an homolog to FKS1 ) of C. glabrata and FKS1 of Candida lusitaniae ( 71 , 72 ), C . tropicalis , and C. krusei ( 73 ) have been reported.…”

“…Another example originates from a C. lusitaniae infection in a young immunocompromised patient with severe enterocolitis and visceral adenoviral disease ( 71 ). C. lusitaniae isolates were recovered from blood cultures and stools over a period of 3 months.…”

“…This study highlighted a very dynamic property of C. lusitaniae , which responded quickly to antifungal exposure. In this specific type of abdominal disease, it is believed that a reservoir of fungal cells was present with mixed MDR genotypes, and, depending on the drug treatment regimen, dominant populations could emerge ( 71 ).…”

Uncommon cause of fungemia in a patient with renal cell cancer

“…[ 14 ] Due to their widespread use over the past decade, emerging resistance to echinocandins has been reported in C lusitaniae . [ 15 , 16 ] A missense mutation in C lusitaniae FKS1 HS1 at position 645 (S645F) has been reported to result in increased MICs of several echinocandins. [ 15 ] Treatment with fluconazole alone has been noted to be very effective especially in patients with solid tumors and in immunocompetent patients.…”

Development of a CRISPR-Cas9 System for Efficient Genome Editing of Candida lusitaniae

“…Mortality due to C. lusitaniae fungemia is 5 to 54% and is often attributed to its relatively high rates of resistance to amphotericin B, which are reported in 22 to 60% of clinical isolates (6, 9). Its emergence as a human pathogen may therefore be on the rise, similar to several other non- albicans Candida species (10), and multidrug resistance to both candins and azoles has recently been reported in clinical isolates (11). C. lusitaniae was also recently found at high levels in the lungs of cystic fibrosis patients, suggesting that this species has the potential to thrive in this niche (12).…”