Role of &lt;I&gt;FKS&lt;/I&gt; Gene in the Susceptibility of Pathogenic Fungi to Echinocandins

Hori, Yasuhiro; Shibuya, Kazutoshi

doi:10.3314/mmj.18.004

Cited by 17 publications

(6 citation statements)

References 108 publications

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“…The precise mechanism of resistance in these isolates is unknown, although echinocandin resistance in other species of Candida is linked to mutations in the drug target protein Fks1 (7). Approximately 3 years into the New York outbreak, these pan-resistant isolates still appear to be rare, but their emergence is concerning.…”

Section: Discussionmentioning

confidence: 99%

Candida aurisIsolates Resistant to Three Classes of Antifungal Medications — New York, 2019

Ostrowsky¹,

Greenko²,

Adams³

et al. 2020

MMWR Morb. Mortal. Wkly. Rep.

162

110

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Candida auris is a globally emerging yeast that causes outbreaks in health care settings and is often resistant to one or more classes of antifungal medications (1). Cases of C. auris with resistance to all three classes of commonly prescribed antifungal drugs (pan-resistance) have been reported in multiple countries (1). C. auris has been identified in the United States since 2016; the largest number (427 of 911 [47%]) of confirmed clinical cases reported as of October 31, 2019, have been reported in New York, where C. auris was first detected in July 2016 (1,2). As of June 28, 2019, a total of 801 patients with C. auris were identified in New York, based on clinical cultures or swabs of skin or nares obtained to detect asymptomatic colonization (3). Among these patients, three were found to have pan-resistant C. auris that developed after receipt of antifungal medications, including echinocandins, a class of drugs that targets the fungal cell wall. All three patients had multiple comorbidities and no known recent domestic or foreign travel. Although extensive investigations failed to document transmission of pan-resistant isolates from the three patients to other patients or the environment, the emergence of pan-resistance is concerning. The occurrence of these cases underscores the public health importance of surveillance for C. auris, the need for prudent antifungal prescribing, and the importance of conducting susceptibility testing on all clinical isolates, including serial isolates from individual patients, especially those treated with echinocandin medications. This report summarizes investigations related to the three New York patients with pan-resistant infections and the subsequent actions conducted by the New York State Department of Health and hospital and long-term care facility partners. Clinical C. auris cases were defined as those in which C. auris was identified in a clinical culture obtained to diagnose or treat disease. Screening cases were defined as those in which C. auris was identified by polymerase chain reaction testing and culture, or by culture only, of a sample from an axilla, groin, or nares swab obtained for the purpose of state public health surveillance (2). To assess ongoing colonization with C. auris, additional swabs were collected over time from patients colonized with C. auris. Wadsworth Center, the New York State public health laboratory, conducted testing to confirm presumptive C. auris isolates from various health care facilities in New York during

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Section: Discussionmentioning

confidence: 99%

Candida aurisIsolates Resistant to Three Classes of Antifungal Medications — New York, 2019

Ostrowsky¹,

Greenko²,

Adams³

et al. 2020

MMWR Morb. Mortal. Wkly. Rep.

162

110

View full text Add to dashboard Cite

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“…Continued studies are needed for further investigation. Furthermore, the emergences of fluconazole-resistant C. albicans and echinocandin-resistant strains due to the FKS gene have been reported [ 26 , 27 ]. As mentioned above, however, no strains suspected of being highly drug-resistant were observed at our hospital.…”

Section: Discussionmentioning

confidence: 99%

Risk Factors and Clinical Characteristics of Patients with Ocular Candidiasis

Sakamoto

Gotoh

Hashimoto

et al. 2022

JoF

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Ocular candidiasis is a critical and challenging complication of candidemia. The purpose of this study was to investigate the appropriate timing for ophthalmologic examinations, risk factors for complications of ocular lesions, and their association with mortality. This retrospective cohort study applied, using multiple logistic regression analysis and Cox regression models, to cases of candidemia (age ≥ 18 years) for patients who underwent ophthalmologic consultation. Of the 108 candidemia patients who underwent ophthalmologic examination, 27 (25%) contracted patients had ocular candidiasis, and 7 experienced the more severe condition of endophthalmitis, which included subjective ocular symptoms. In most cases, the initial ophthalmologic examination was performed within one week of the onset of candidiasis with a diagnosis of ocular candidiasis, but in three cases, the findings became apparent only after a second examination within 7–14 days after onset of candidiasis. The independent risk factor extracted for the development of ocular candidiasis was the isolation of C. albicans (OR, 4.85; 95% CI, 1.58–14.90), unremoved CVC (OR, 10.40; 95% CI, 1.74–62.16), and a high βDG value (>108.2 pg/mL) (HR, 2.83; 95% CI = 1.24–6.27). Continuous ophthalmologic examination is recommended in cases of candidemia with the above risk factors with an initial examination within 7 days of onset and a second examination 7–14 days after onset.

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“…On the other hand, FKS1 expression predominantly occurs during growth on glucose and is constitutively regulated during the cell cycle [68]. The disruption of both alleles of FKS1 and FKS2 is lethal [68,69], suggesting that (i) both proteins are component of the complex and (ii) that both subunits are essential and have overlapping function [7,68]. In haploid organisms such as C. glabrata, the disruption of FKS1 and FKS2 is also lethal but the disruption of FKS1 and FKS3 or FKS2 and FKS3 is not.…”

Section: Rezafungin and The Older Echinocandin's Target: The β-Glucan Synthase Complexmentioning

confidence: 99%

Rezafungin—Mechanisms of Action, Susceptibility and Resistance: Similarities and Differences with the Other Echinocandins

García‐Effrón

2020

JoF

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Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) echinocandins as it has better tissue penetration, better pharmacokinetic/phamacodynamic (PK/PD) pharmacometrics, and a good safety profile. It is much more stable in solution than the older echinocandins, making it more flexible in terms of dosing, storage, and manufacturing. These properties would allow rezafungin to be administered once-weekly (intravenous) and to be potentially administered topically and subcutaneously. In addition, higher dose regimens were tested with no evidence of toxic effect. This will eventually prevent (or reduce) the selection of resistant strains. Rezafungin also has several similarities with older echinocandins as they share the same in vitro behavior (very similar Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC50) and half enzyme maximal inhibitory concentration 50% (IC50)) and spectrum, the same target, and the same mechanisms of resistance. The selection of FKS mutants occurred at similar frequency for rezafungin than for anidulafungin and caspofungin. In this review, rezafungin mechanism of action, target, mechanism of resistance, and in vitro data are described in a comparative manner with the already approved echinocandins.

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Role of <I>FKS</I> Gene in the Susceptibility of Pathogenic Fungi to Echinocandins

Cited by 17 publications

References 108 publications

Candida aurisIsolates Resistant to Three Classes of Antifungal Medications — New York, 2019

Candida aurisIsolates Resistant to Three Classes of Antifungal Medications — New York, 2019

Risk Factors and Clinical Characteristics of Patients with Ocular Candidiasis

Rezafungin—Mechanisms of Action, Susceptibility and Resistance: Similarities and Differences with the Other Echinocandins

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