In vitro and in vivo interaction of caspofungin with isavuconazole against Candida auris planktonic cells and biofilms

Nagy, Fruzsina; Tóth, Zoltán; Nyikos, Fanni; Forgács, Lajos; Jakab, Ágnes; Borman, Andrew M.; Majoros, László; Kovács, Renátó

doi:10.1093/mmy/myab032

Cited by 15 publications

(35 citation statements)

References 42 publications

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“…One-day-old biofilms were prepared as described previously (Kovács et al 2016, Nagy et al 2021). Briefly, following 48 h culturing on Sabouraud dextrose agar (Lab M Ltd., Bury, United Kingdom), C. auris cells were harvested by centrifugation (3000 g for 5 min), washed three times in sterile physiological saline, and the final density of the inoculums was adjusted in RPMI-1640 broth to 1 × 10 6 cells/mL.…”

Section: Methodsmentioning

confidence: 99%

“…2016, Nagy et al . 2020, Nagy et al . 2021) and are presented as the median value of three independent experiments per isolate.…”

Section: Methodsmentioning

confidence: 99%

“…Drug-drug interactions between caspofungin and posaconazole were assessed by the two-dimensional checkerboard broth microdilution assay, as previously described (Meletiadis et al 2005, Kovács et al 2016, Nagy et al 2020, Nagy et al 2021, Bidaut et al 2021). Planktonic and sessile cells were prepared with 2 × 10 4 cells/mL and 1 × 10 6 cells/mL, respectively, containing different concentrations of each drug combination.…”

Section: Methodsmentioning

confidence: 99%

“…Several investigators have proposed combination-based therapeutic approaches using existing drugs to overcome the difficult-to-treat C. auris- related infections, including biofilm associated cases, increasing the likelihood of therapeutic success (Bidaud et al . 2020, Brennan-Krohn et al 2021, Caballero et al 2021, Nagy et al 2021, Vitale 2021). Based on previously published results, the combination of caspofungin and posaconazole has shown high efficacy against both C. albicans and Candida glabrata echinocandin-susceptible and -resistant isolates (Chen et al 2013, Denardi et al 2017, Khalifa et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Synergistic interaction of caspofungin combined with posaconazole against FKS wild-type and mutant Candida auris planktonic cells and biofilms

Balla

Kovács

Balázs

et al. 2022

Preprint

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The in vitro efficacy of caspofungin against FKS wild type and mutant Candida auris isolates was determined in the presence of posaconazole. Drug–drug interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss independence model and a LIVE/DEAD viability assay. Median planktonic minimum inhibitory concentrations (pMICs) of C. auris isolates were between 0.5 and >2 mg/L for caspofungin and between 0.125 and >0.25mg/L for posaconazole. Median pMICs for caspofungin and posaconazole in combination showed a 4- to 256-fold decrease compared to caspofungin and a 2- to 512-fold decrease compared to posaconazole alone. The median sessile minimum inhibitory concentrations (sMICs) of isolates ranged from 32 to >32 mg/L and from 0.06 to >2 mg/L for caspofungin and posaconazole, respectively. Median sMICs for caspofungin and posaconazole in combination showed an 8- to 128-fold decrease compared to caspofungin and a 4- to 512-fold decrease compared to posaconazole alone. Caspofungin and posaconazole showed a synergistic interaction, especially against sessile cells (FICI from 0.033–0.375 and 0.091–0.5, and Bliss cumulative synergy volumes were 6.96 and 32.39 for echinocandin-susceptible and -resistant isolates, respectively). In line with the checkerboard-based findings, synergistic interactions were confirmed by a fluorescent microscopic LIVE/DEAD viability assay. The caspofungin-exposed (4 mg/L) C. auris biofilms exhibited increased cell death in the presence of posaconazole (0.03 mg/L) compared to untreated, caspofungin-exposed and posaconazole-treated sessile cells. The disrupted biofilm structure and increase in cell death was observed for both echinocandin-susceptible and echinocandin-resistant isolates. Despite the favourable effect of caspofungin in the presence of posaconazole, further in vivo studies are needed to confirm the clinical therapeutic potential of this combination when treating C. auris.Contribution to the fieldCandida auris is an emerging fungal pathogen, presumably related to global warming, which is associated with nosocomial infections and is considered a serious health threat worldwide. The treatment of C. auris infections is challenging due to the high level of drug resistance against the traditional antifungal agents. Given the low frequency of resistance to echinocandins, they are recommended as first-line therapy for the management of C. auris infections; however, treatment is complicated by the development of resistance in patients receiving long-term echinocandin treatment. In addition, the biofilm forming ability of this species further complicates the echinocandin-based therapeutic strategies. Combination-based approaches using existing drugs are viable alternatives to overcome the difficult-to-treat C. auris-related infections, including biofilm associated cases. In this study, we examined the in vitro efficacy of caspofungin and posaconazole against FKS wild-type and mutant C. auris planktonic cells and biofilms using classic checkerboard-based investigations and fluorescent imaging. Based on our results, the efficacy of caspofungin and posaconazole is unquestionable, having been confirmed against biofilms, especially in the case of FKS mutants at clinically achievable and safe drug concentrations. This study suggests that the administration of caspofungin with posaconazole may help to expand potential treatment strategies.

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Section: Methodsmentioning

confidence: 99%

“…2016, Nagy et al . 2020, Nagy et al . 2021) and are presented as the median value of three independent experiments per isolate.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergistic interaction of caspofungin combined with posaconazole against FKS wild-type and mutant Candida auris planktonic cells and biofilms

Balla

Kovács

Balázs

et al. 2022

Preprint

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“…Others have performed in vitro studies of antifungal combinations with isavuconazole and an echinocandin against isolates of C. auris . These investigators discovered synergy in many of the isolates tested, suggesting that combination therapy with isavuconazole and an echinocandin is a treatment option to consider for pan-resistant C. auris [ 28 , 29 ]. The combination of isavuconazole and an echinocandin has been studied in vitro against other Candida species, and similar results were demonstrated [ 30 ].…”

Section: Isavuconazolementioning

confidence: 99%

Antifungal Resistance and the Role of New Therapeutic Agents

Logan

Wolfe

Williamson

2022

Curr Infect Dis Rep

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Purpose of Review Advances in health care over time have led to an evolution in the epidemiology of invasive fungal infections. There is an increasing concern for antifungal resistance and emergence of less common fungal species for which optimal therapies are not well defined. The purpose of this review is to describe mechanisms of antifungal resistance and to evaluate the modern role of new and investigational antifungals. Recent Findings Isavuconazole and ibrexafungerp represent the two newest antifungal agents. Evidence from in vivo and in vitro studies has been published recently to help define their place in therapy and potential roles in treating resistant fungi. Isavuconazole is a broad-spectrum triazole antifungal with evidence to support its use in invasive aspergillosis and mucormycosis. Its utility in treating voriconazole-resistant Candida should be confirmed with susceptibility testing if available. Ibrexafungerp is an oral glucan synthase inhibitor with little cross-resistance among currently available antifungals, including echinocandins. It is a promising new agent for invasive candidiasis, including azole-resistant Candida species, and in combination therapy with voriconazole for aspergillosis. Multiple antifungals, some with novel mechanisms, are in development, including rezafungin, oteseconazole, olorofim, fosmanogepix, and opelconazole. Summary Both isavuconazole and ibrexafungerp are welcome additions to the arsenal of antifungals, and the prospect of more antifungal options in the future is encouraging. Such an array of antifungals will be important as antifungal resistance continues to expand alongside evolving medical practices. However, managing resistant fungal infections will grow in complexity as the unique role of each new agent is defined.

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PK/PD modeling and simulation of the in vitro activity of the combinations of isavuconazole with echinocandins against Candida auris

Caballero

Eraso

Quindós

et al. 2023

CPT Pharmacom & Syst Pharma

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In vitro combination of echinocandins and isavuconazole against the emerging species Candida auris is mainly synergistic. However, this combination has not been evaluated in clinical settings. A pharmacokinetic/pharmacodynamic modeling and simulation approach based on in vitro data may be helpful to further study the therapeutic potential of these combinations. Therefore, the aims of this study were to characterize the time course of growth and killing of C. auris in response to the combination of the three approved echinocandins and isavuconazole using a semimechanistic model and to perform model-based simulations in order to predict the in vivo response to combination therapy. In vitro static time-kill curve data for isavuconazole and echinocandins combinations against six blood isolates of C. auris were best modeled considering the total killing of the fungal population as dependent on the additive effects of both drugs. Once assessed, the predictive performance of the model using simulations of different dosing and fungal susceptibility scenarios were conducted. Model-based simulations revealed that none of the combinations at standard or higher dosages would be effective against the studied isolates of C. auris and it was predicted that the combinations of isavuconazole with anidulafungin or caspofungin would be effective for minimum inhibitory concentrations up to 0.03 and 0.06 mg/L respectively, whereas the combination with micafungin would lead to treatment failure.The current approach highlights the importance of bridging the in vitro results to the clinic. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?In previous in vitro studies, synergism was demonstrated for the combination of isavuconazole with echinocandins against Candida auris.

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In vitro and in vivo interaction of caspofungin with isavuconazole against Candida auris planktonic cells and biofilms

Cited by 15 publications

References 42 publications

Synergistic interaction of caspofungin combined with posaconazole against FKS wild-type and mutant Candida auris planktonic cells and biofilms

Synergistic interaction of caspofungin combined with posaconazole against FKS wild-type and mutant Candida auris planktonic cells and biofilms

Antifungal Resistance and the Role of New Therapeutic Agents

PK/PD modeling and simulation of the in vitro activity of the combinations of isavuconazole with echinocandins against Candida auris

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