Evaluation of the Synergistic Activity of Antibacterial and Antifungal Drugs against Candida auris Using an Inkjet Printer-Assisted Method

Brennan-Krohn, Thea; Friar, Liam; Ditelberg, Sarah

doi:10.1128/aac.00268-21

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…Treatment of pan-resistant C. auris strains is a clinical challenge. Combination antifungal treatment yielded mixed results in laboratory testing and has not been systematically evaluated in clinical settings [ 115 , 118 , 123 , 131 , 132 , 133 , 134 , 135 ]. Some in vitro studies showed that effective treatments against pan-drug-resistant C. auris are flucytosine combinations with amphotericin B, azoles or echinocandins, or amphotericin B and echinocandin combined [ 118 , 134 , 135 ].…”

Section: C Auris Antifungal Resistance and Therapeutic Optionsmentioning

confidence: 99%

Navigating the New Reality: A Review of the Epidemiological, Clinical, and Microbiological Characteristics of Candida auris, with a Focus on Children

Ashkenazi‐Hoffnung

Danziger

2023

JoF

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During the past decade, Candida auris emerged across the world, causing nosocomial outbreaks in both pediatric and adult populations, particularly in intensive care settings. We reviewed the epidemiological trends and the clinical and microbiological characteristics of C. auris infection, focusing on the pediatric population. The review is based on 22 studies, which included about 250 pediatric patients with C. auris infection, across multiple countries; neonates and premature babies were the predominant pediatric patient group affected. The most common type of infection reported was bloodstream infection, which was associated with exceptionally high mortality rates. Antifungal treatment varied widely between the patients; this signifies a serious knowledge gap that should be addressed in future research. Advances in molecular diagnostic methods for rapid and accurate identification and for detection of resistance may prove especially valuable in future outbreak situations, as well as the development of investigational antifungals. However, the new reality of a highly resistant and difficult-to-treat pathogen calls for preparedness of all aspects of patient care. This spans from laboratory readiness, to raising awareness among epidemiologists and clinicians for global collaborative efforts to improve patient care and limit the spread of C. auris.

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Section: C Auris Antifungal Resistance and Therapeutic Optionsmentioning

confidence: 99%

Navigating the New Reality: A Review of the Epidemiological, Clinical, and Microbiological Characteristics of Candida auris, with a Focus on Children

Ashkenazi‐Hoffnung

Danziger

2023

JoF

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“…Several in vitro and in vivo studies on antifungal drugs have shown that combinations can broaden the coverage, increase the fungicidal effect in unresponsive cases and significantly decrease the risk of the emergence of acquired resistance [ 15 , 16 , 17 , 18 ]. In addition, combination-based therapeutic approaches in addition to monotherapy are also recommended in situations such as those depending on the type and site of infection and the patient’s condition [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Echinocandin resistance is associated with mutations in the hot-spot regions of FKS genes, which encode the catalytic subunit of the 1,3-β-d-glucan synthase enzyme [ 14 ]. 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 [ 15 , 16 , 17 , 18 , 19 ]. Drug–drug combinations enhance efficacy and specificity compared to monotherapy; in addition, they can slow the evolution of resistance [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic Interaction of Caspofungin Combined with Posaconazole against FKS Wild-Type and Mutant Candida auris Planktonic Cells and Biofilms

et al. 2022

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Candida auris is a potential multidrug-resistant pathogen able to cause biofilm-associated outbreaks, where frequently indwelling devices are the source of infections. The number of effective therapies is limited; thus, new, even-combination-based strategies are needed. Therefore, the in vitro efficacy of caspofungin with posaconazole against FKS wild-type and mutant Candida auris isolates was determined. The interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss model, and a LIVE/DEAD assay. Planktonic minimum inhibitory concentrations (pMICs) for the caspofungin–posaconazole combination showed a 4- to 256-fold and a 2- to 512-fold decrease compared to caspofungin and posaconazole alone, respectively. Sessile minimum inhibitory concentrations (sMICs) for caspofungin and posaconazole in combination showed an 8- to 128-fold and a 4- to 512-fold decrease, respectively. The combination showed synergy, especially against biofilms (FICIs were 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). 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 biofilms. Despite the favorable effect of caspofungin with posaconazole, in vivo studies are needed to confirm the therapeutic potential of this combination in C. auris-associated infections.

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“…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%

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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Evaluation of the Synergistic Activity of Antibacterial and Antifungal Drugs against Candida auris Using an Inkjet Printer-Assisted Method

Cited by 4 publications

References 36 publications

Navigating the New Reality: A Review of the Epidemiological, Clinical, and Microbiological Characteristics of Candida auris, with a Focus on Children

Navigating the New Reality: A Review of the Epidemiological, Clinical, and Microbiological Characteristics of Candida auris, with a Focus on Children

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

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