Rapid Emergence of Echinocandin Resistance during Candida kefyr Fungemia Treatment with Caspofungin

Abstract

e Echinocandin drugs are widely used for the treatment of candidemia. Resistance is considered rare, and only a few cases of breakthrough candidiasis in patients receiving echinocandin have been reported worldwide. We report here for the first time a Candida kefyr isolate that acquired echinocandin resistance very rapidly after the initiation of caspofungin treatment for candidemia. We characterized the FKS gene mutation responsible for the resistance via the comparison of isolates sampled before and during treatment.A 61-year-old woman was admitted to the hematological unit at Pitié-Salpêtrière Hospital (Paris, France) for acute myeloid leukemia. The patient was not then receiving and had no history of receiving antifungal drugs. During chemotherapy-induced aplasia, a blood culture sampled at day 1 yielded positive for yeast at day 3. Considering the clinical condition of the patient, echinocandin antifungal therapy was chosen. Treatment by caspofungin was initiated on day 3 (70 mg the first day and then 50 mg/day; patient weight, 60 kg). Analysis of the strain with API 20C (bioMérieux, France) strips and mass spectrometry (Bruker Daltonics, Germany) clearly identified Candida kefyr (teleomorph, Kluyveromyces marxianus). Before the determination of the MICs, caspofungin treatment was left unchanged. The MICs for caspofungin, micafungin, and anidulafungin as determined by Etest (bioMérieux) were 0.06, 0.03, and 0.03 g/ml, respectively. For fluconazole, the MIC was 0.25 g/ml. As the patient's condition did not improve, treatment was switched to fluconazole at day 10. A blood culture sampled the same day was positive for yeast at day 11. Surprisingly, this culture gave C. kefyr again. For this isolate, the MICs for caspofungin, micafungin, and anidulafungin by Etest were 2, 4, and 8 g/ml, respectively. It should be noted that the determination of MIC by the CLSI reference method showed similar results (Table 1), but considering the recently proposed epidemiological cutoff value (ECV) for echinocandins against C. kefyr (1), for the initial isolate with low MIC echinocandin values, the MIC for caspofungin was above the ECV, whereas those for anidulafungin and micafungin were below. While receiving fluconazole, a blood culture sampled at day 19 was positive for yeast at day 21, and this time Candida krusei was identified. Treatment was then switched to voriconazole at day 23. The patient died at day 30. Of note, the two candidemias were surely of digestive origin; a stool sample collected a few days before the first candidemia was positive for both C. kefyr and C. krusei.Methods, results, and discussion. Faced with both microbiological resistance and clinical therapeutic failure, we decided to compare the hot spots (HS) of the FKS gene sequences of the two C. kefyr strains, the first identified in the blood culture sampled at day 1 (low echinocandin MIC) and the second at day 10 during caspofungin treatment (high echinocandin MIC). Resistance to echinocandin consistently involves these short FKS sequences that code f...

Epidemiology of Candida kefyr in Patients with Hematologic Malignancies

“…More detailed study of these isolates (J. F. Staab, D. Neofytos, P. Rhee, C. Jimenez-Ortigosa, S. X. Zhang, D. S. Perlin, and K. A. Marr, submitted for publication) documented variable MICs to different echinocandins. Also, other investigators have observed C. kefyr resistance to echinocandins developing rapidly under treatment (37). Although our risk factor analysis identified administration of azoles or amphotericin B to be protective against C. kefyr colonization, it appears that C. kefyr has the propensity to develop resistance to all classes of antifungals, based on the MICs observed in the IC C. kefyr isolates in our study.…”

Using Aspergillus nidulans To Identify Antifungal Drug Resistance Mutations

“…Fifth, if multiple mutations were necessary for drug resistance, antifungal adaptation that required a particular combination of mutations would be expected to be extremely rare. Taken together, several lines of evidence besides our CFW study show that drug resistance based on protein function can emerge quickly given the appropriate selection pressure (11,13,33), consistent with single-gene mutations. In contrast, resistance to polyenes that target ergosterol distribution, rather than its synthesis, has been relatively durable, although even it has been overcome recently (33).…”

“…They did not identify the mutated genes, probably due to factors mentioned above. Second, echinocandin resistance mutations are typically at single sites in FKS1 (10)(11)(12). Third, single mutations in Erg11 lead to resistance to azoles (32).…”

“…The strong adaptation ability of fungi is well documented (13)(14)(15)(16), so it was not surprising to see antifungal drug resistance emerging quickly. Mutation hot spots in FKS1, which encodes beta-glucan synthase, were detected in some of the resistant strains but not in all (10)(11)(12). Our strategy can efficiently identify mutations in the latter group.…”

“…Cowen (7) notes that the effectiveness of all existing antifungal drugs is reduced by resistant strains. Especially for echinocandins, clinically resistant strains were isolated shortly after their launch (11,12). The strong adaptation ability of fungi is well documented (13)(14)(15)(16), so it was not surprising to see antifungal drug resistance emerging quickly.…”