PubMed · 430296
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J R Poliner, E B Wilkins, G W Fernald. 1979. Localized osseous cryptococcosis.. https://doi.org/10.1016/s0022-3476(79)80020-7
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Clinical isolates of Candida auris show a high prevalence of resistance to Amphotericin B (AmB)-an uncommon trait in most Candida species. Alterations in ergosterol biosynthesis can contribute to acquired AmB resistance in C. auris laboratory strains but are rarely seen in clinical isolates. In this study, we experimentally evolved two drug-susceptible Clade II isolates of C. auris to develop AmB resistance. The evolved strains displayed a four to eight fold increase in MIC50 compared to the parental cells. We analyzed changes in their karyotype, genome, lipidome, and transcriptome associated with this acquired resistance. In one lineage, AOX2 was upregulated, and its deletion reversed the AmB resistance phenotype. The aox2Δ mutant also failed to evolve AmB resistance under experimental conditions. In the same lineage, restoring the UPC2 S332R and RTG3 S101T mutations to the wild-type allele restored AmB susceptibility. In another lineage, the ergosterol and sphingolipid pathways were observed to play a critical role, and upregulation of the ERG genes elevated the total sterol content, while significant downregulation of HSX11 (glucosylceramide synthase) resulted in lower levels of glucosylceramides. To our knowledge, this study is the first to show that AmB resistance in C. auris can be acquired through mechanisms both dependent on or independent of sterol content modulation, highlighting Aox2 and Upc2 as key regulators of amphotericin resistance.
Twenty-eight pathogenic isolates, 4 each of Candida albicans, C. lusitaniae, C. parapsilosis, Cryptococcus neoformans, Torulopsis glabrata and Trichosporon beigelii were tested for their in vitro sensitivity to amphotericin B (AmB), hamycin (HA) and their novel water-soluble compounds, namely JAI-AmB (oral and injectable; patents pending) and JAI-HA (Jaimycin Inc., Walnut Creek, Calif., USA), using a standard double-dilution broth (1 ml/tube) procedure. The 2 novel compounds, namely JAI-AmB and JAI-HA, contain one twenty-fifth (w/w) of the AmB and HA, respectively. Results showed that the minimal inhibitory concentrations (MICs) of AmB for all species, except C. lusitaniae and Tr. beigelii (3.125-6.25 micrograms/ml), were 0.195-1.56 micrograms/ml. The values of JAI-AmB (oral) for C. albicans, C. parapsilosis, Cr. neoformans and To. glabrata ranged from 0.78 to 25 micrograms/ml. The MICs of JAI-AmB (oral) for the other yeasts were 100 micrograms/ml. All of the yeasts yielded higher MICs (3.125-100 micrograms/ml) against JAI-AmB (injectable) than the JAI-AmB (oral) preparation. Except for C. parapsilosis (MICs 25-100 micrograms/ml), all of the other species showed greater sensitivity to the parent HA (0.195-100 micrograms/ml) than AmB. The values for JAI-HA ranged from 0.195 to 100 micrograms/ml for all isolates, except C. tropicalis (100 micrograms/ml). Based on our in vitro findings, in vivo efficacies of JAI-AmB and JAI-HA should be carried out.
Systemic Candida infections are a major cause of infectious morbidity and mortality during chemotherapy-induced neutropenia. Because of the unreliability of conventional diagnostic tests to detect systemic infection early in its course, treatment of established disseminated Candida infection has been generally disappointing with mortality rates of 60-80% in leukemia and bone marrow transplant patients and 30-40% in solid tumor patients. The use of empiric amphotericin B in patients with fever not responding to empiric antibacterial agents has been shown to be successful in reducing morbidity and mortality from fungal infections. However, its toxicity has mitigated the success of this approach. Fluconazole given prophylactically at the institution of chemotherapy has been shown to be a safe and effective alternative. It, however, is not active against all fungal species, especially Aspergillus and some of the less virulent Candida species. Some centers have reported break-through infections by these less susceptible organisms. Whether or not these limitations in its spectrum of activity will limit its usefulness in the future remains unanswered at this time and could pose a cloud to an otherwise bright promise.