Clinical perspectives on echinocandin resistance among Candida species

Shields, Ryan K.; Nguyen, M. Hong; Clancy, Cornelius J.

doi:10.1097/qco.0000000000000215

Cited by 64 publications

(56 citation statements)

References 55 publications

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“…In addition to the emergence of azole resistance in Candida spp., the rates of resistance to the echinocandins are also increasing (35). Particularly worrisome is the fact that this is most common in strains of C. glabrata, a species with high rates of azole resistance.…”

Section: Resultsmentioning

confidence: 99%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

Antimicrob Agents Chemother

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gOnly one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans, non-albicans Candida spp., Cryptococcus neoformans), molds (e.g., Fusarium, Mucor), and dimorphic fungi (Blastomyces, Histoplasma, and Coccidioides) with MICs of 2 to 4 g/ml. AR-12 is also active against azole-and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole-and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.T he treatment of life-threatening invasive fungal infections (IFIs) remains a significant challenge to modern medicine (1, 2). Two primary factors contribute to the difficult nature of IFI therapy. First, most IFIs affect people with compromised immune function, and therefore, IFI patients are more reliant on the efficacy of the antifungal drug than immunocompetent patients. Second, the development of effective antifungal drugs is difficult, because many fundamental biological processes are highly conserved between fungi and humans (3). Consequently, identifying molecules that kill the pathogen and spare the host is very challenging. Currently, only three primary classes of antifungal drugs are in clinical use: (i) azole ergosterol biosynthesis inhibitors (e.g., fluconazole [FLU]), (ii) polyene ergosterol binding agents (e.g., amphotericin B), and (iii) echinocandin 1,3-␤-D-glucan synthase inhibitors (e.g., caspofungin). The number of antifungal drugs pales in comparison to the number of distinct classes of antimicrobial agents, and, in fact, there are currently more classes of antiretroviral agents available for the treatment of HIV/AIDS than classes of antifungal drugs (2).The pace of antifungal drug development has been extremely slow. For example, the most recent addition to the antifungal pharmacopeia, the echinocandins, was discovered in the early 1970s and introduced into clinical practice in the early 2000s (3). Furthermore, no new drugs for the treatment of cryptococcal meningitis, one of the most important causes of infectious disease-related deaths in HIV/AIDS patients (4), have been introduced into clinical practice in more than 20 years. In fact, the current gold standard therapy is based on drugs (amphotericin B an...

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Section: Resultsmentioning

confidence: 99%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

Antimicrob Agents Chemother

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“…Due to insufficient data available, micafungin is currently not recommended for patients with severe hepatic impairment [20]. In addition, although micafungin has demonstrated efficacy and safety at high doses, the potential emergence of echinocandin resistance should be considered in future clinical trials [43]. …”

Section: Discussionmentioning

confidence: 99%

Effectiveness and Safety of Micafungin in Managing Invasive Fungal Infections among Patients in Greece with Hematologic Disorders: The ASPIRE Study

et al. 2019

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Introduction Invasive candidiasis (IC) can be a life-threatening infection in immunocompromised patients, particularly those with cancer, hematologic diseases and/or hematopoietic stem cell transplantation (HSCT) recipients. The objective of this study was to evaluate the effectiveness of micafungin in patients with hematologic malignancies or HSCT recipients, relevant to clinical presentation of IC, in real-life practice in Greece. Methods ASPIRE was a phase IV, multicenter, non-interventional, prospective cohort study, conducted at ten tertiary hospitals in Greece, in adults with hematologic disease. Micafungin treatment for IC or prophylaxis for Candida infection was administered per standard clinical practice until a clinical outcome (success or failure) was reached. Treatment success was defined by the EORTC/MSG criteria for invasive fungal infections (IFI) and was assessed by the investigator. Treatment discontinuation and safety were also evaluated. Results One hundred forty-three patients were enrolled. Median age was 62; 85 (59.4%) patients were male, and 133 (93.0%) had Greek ethnicity. One hundred twenty-six (88.1%) patients had hematologic malignancies, and 21 (14.7%) had received HSCT. Prophylaxis was administered to 74 (51.7%) patients [median (range) dose: 50 (50–150) mg/day] with no signs of IFI. Overall, 52 (36.4%) patients with possible IFI at baseline received micafungin treatment [100 (50–125) mg/day] versus 12 (17.2%) with probable [100 (75–150) mg/day] and 5 (3.5%) with confirmed [125 (100–150) mg/day] IFI. Treatment success was 91.6% (95% CI 85.80–95.59; n = 131) overall and 90.5% ( n = 67) in patients receiving prophylaxis. Median time on treatment was 13 days. Treatment discontinuation ( n = 26; 18.2%) was not related to adverse events. No treatment-related serious adverse events were reported. Conclusion Micafungin treatment for IC or prophylaxis for Candida infection was effective and well tolerated in patients with hematologic disorders in clinical practice in Greece. These results demonstrate that micafungin could be used more widely for prophylaxis. Further work is required to determine the efficacy and safety of micafungin for the management of IFIs in hematologic settings. Funding Astellas Pharma Inc.

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“…Resistance to echinocandins has been mainly described in C. glabrata and is caused by mutations in the FKS genes that encode the target enzyme 1,3‐D‐glucan synthase. Prolonged exposure to echinocandins is the major factor in the onset of resistance . In our study, despite the increase in echinocandin use over the years, one single C. glabrata isolate was resistant.…”

Section: Discussionmentioning

confidence: 99%

Changes in the distribution of colonising and infecting Candida spp. isolates, antifungal drug consumption and susceptibility in a French intensive care unit: A 10‐year study

Sasso

Roger

Sasso³

et al. 2017

Mycoses

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Monitoring fungal ecology and resistance to antifungal agents within intensive care units (ICU) is essential for the management of invasive fungal infections. Therefore, a retrospective descriptive study was carried in the ICU of Nimes University Hospital, France, from 2007 to 2016. As the majority of invasive fungal infections in ICU are caused by Candida species, the study objectives were to describe Candida species distribution, to assess candidaemia incidence and to monitor the antifungal drug susceptibility of Candida isolates and the consumption of antifungal agents. Among the recorded invasive Candida infections (n=244), 43% were intra-abdominal and 22% bloodstream infections. Candida albicans was the most frequent species (55.8%), followed by Candida glabrata (14.1%), Candida tropicalis (10%), Candida parapsilosis (8%) and Candida krusei (5.3%). Candidaemia incidence was 4.49 per 1000 admissions. The mean consumption of antifungal agents was of 170.5 defined daily doses (DDD) for 1000 hospital days (HD) per year. Changes in antifungal drug consumption were observed, with an increased use of echinocandins (from 17.96 DDD/1000 HD in 2007 to 48.76 DDD/1000 HD in 2016), and the total treatment cost tripled during the study period. No significant change in fungal ecology or in the emergence of resistant species was observed; indeed, only 1.1% of isolates presented an unusual resistance to antifungal agents.

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Clinical perspectives on echinocandin resistance among Candida species

Cited by 64 publications

References 55 publications

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Effectiveness and Safety of Micafungin in Managing Invasive Fungal Infections among Patients in Greece with Hematologic Disorders: The ASPIRE Study

Changes in the distribution of colonising and infecting Candida spp. isolates, antifungal drug consumption and susceptibility in a French intensive care unit: A 10‐year study

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