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

AbstractThe in vitro and in vivo efficacy of caspofungin was determined in combination with isavuconazole against Candida auris. Drug–drug interactions were assessed utilising the fractional inhibitory concentration indices (FICIs), the Bliss independence model and an immunocompromised mouse model. Median planktonic minimum inhibitory concentrations (pMICs) of 23 C. auris isolates were between 0.5 and 2 mg/L and between 0.015 and 4 mg/L for caspofungin and isavuconazole, respectively. Median pMICs for caspofungin and isavuconazole in combination showed 2–128-fold and 2–256-fold decreases, respectively. Caspofungin and isavuconazole showed synergism in 14 out of 23 planktonic isolates (FICI range 0.03–0.5; Bliss cumulative synergy volume range 0–4.83). Median sessile MICs (sMIC) of 14 biofilm-forming isolates were between 32 and >32 mg/L and between 0.5 and >2 mg/L for caspofungin and isavuconazole, respectively. Median sMICs for caspofungin and isavuconazole in combination showed 0–128-fold and 0-512-fold decreases, respectively. Caspofungin and isavuconazole showed synergistic interaction in 12 out of 14 sessile isolates (FICI range 0.023–0.5; Bliss cumulative synergy volume range 0.13–234.32). In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were more than 3 log volumes in mice treated with combination of 1 mg/kg caspofungin and 20 mg/kg isavuconazole daily; this difference was statistically significant compared with control mice (p<0.001). Despite the favourable effect of isavuconazole in combination with caspofungin, further studies are needed to confirm the therapeutic advantage of this combination when treating an infection caused by C. auris.

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Farnesol increases the activity of echinocandins against Candida auris biofilms

Medical Mycology ◽

10.1093/mmy/myz057 ◽

2019 ◽

Vol 58 (3) ◽

pp. 404-407 ◽

Cited By ~ 6

Author(s):

Fruzsina Nagy ◽

Zoltán Tóth ◽

Lajos Daróczi ◽

Adrien Székely ◽

Andrew M Borman ◽

...

Keyword(s):

Inhibitory Concentration ◽

Candida Auris ◽

Independence Model ◽

Microscope Images ◽

Vitro Effect ◽

Volume Range ◽

Quorum Sensing Molecule ◽

Bliss Independence ◽

Scanning Electron

Abstract Candida auris biofilms exhibit decreased susceptibility to echinocandins, which is associated with poorer clinical outcomes. Farnesol is a quorum-sensing molecule enhancing the activity of antifungals; therefore, we evaluated the in vitro effect of farnesol with anidulafungin, caspofungin, or micafungin against biofilms using fractional inhibitory concentration indexes (FICI), Bliss independence model, LIVE/DEAD-assay and scanning electron microscopy. Based on mathematical models, farnesol caused synergism in eleven out of twelve cases (FICIs range 0.133-0.507; Bliss synergy volume range 70.39–204.6 μM2%). This was confirmed by microscope images of combination-exposed biofilms. Our study showed the prominent effect of farnesol with echinocandins against C. auris biofilms.

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Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: In Vitro and In Vivo Correlations of the Concentration- and Dose- Dependent Interactions between Anidulafungin and Voriconazole by Bliss Independence Drug Interaction Analysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00329-09 ◽

2009 ◽

Vol 53 (6) ◽

pp. 2382-2391 ◽

Cited By ~ 65

Author(s):

Vidmantas Petraitis ◽

Ruta Petraitiene ◽

William W. Hope ◽

Joseph Meletiadis ◽

Diana Mickiene ◽

...

Keyword(s):

Drug Interaction ◽

Interaction Analysis ◽

Invasive Pulmonary Aspergillosis ◽

Pulmonary Aspergillosis ◽

Treatment Groups ◽

Synergistic Interactions ◽

Significant Difference ◽

Bliss Independence

ABSTRACT We studied the antifungal activity of anidulafungin (AFG) in combination with voriconazole (VRC) against experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits and further explored the in vitro and in vivo correlations by using Bliss independence drug interaction analysis. Treatment groups consisted of those receiving AFG at 5 (AFG5 group) and 10 (AFG10 group) mg/kg of body weight/day, VRC at 10 mg/kg every 8 h (VRC group), AFG5 plus VRC (AFG5+VRC group), and AFG10 plus VRC (AFG10+VRC group) and untreated controls. Survival throughout the study was 60% for the AFG5+VRC group, 50% for the VRC group, 27% for the AFG10+VRC group, 22% for the AFG5 group, 18% for the AFG10 group, and 0% for control rabbits (P < 0.001). There was a significant reduction of organism-mediated pulmonary injury, measured by infarct scores, lung weights, residual fungal burdens, and galactomannan indexes, in AFG5+VRC-treated rabbits versus those treated with AFG5 and VRC alone (P < 0.05). In comparison, AFG10+VRC significantly lowered only infarct scores and lung weights in comparison to those of AFG10-treated animals (P < 0.05). AFG10+VRC showed no significant difference in other outcome variables. Significant Bliss synergy was found in vivo between AFG5 and VRC, with observed effects being 24 to 30% higher than expected levels if the drugs were acting independently. These synergistic interactions were also found between AFG and VRC in vitro. However, for AFG10+VRC, only independence and antagonism were observed among the outcome variables. We concluded that the combination of AFG with VRC in treatment of experimental IPA in persistently neutropenic rabbits was independent to synergistic at a dosage of 5 mg/kg/day but independent to antagonistic at 10 mg/kg/day, as assessed by Bliss independence analysis, suggesting that higher dosages of an echinocandin may be deleterious to the combination.

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In vitro and in vivo synergistic interactions between the flavonoid rutin with paracetamol and non-steroidal anti-inflammatory drugs

Archives of Medical Research ◽

10.1016/j.arcmed.2021.03.007 ◽

2021 ◽

Author(s):

Juan Ramón Zapata-Morales ◽

Angel Josabad Alonso-Castro ◽

Gloria Sarahí Muñoz-Martínez ◽

María Mayela Martínez-Rodríguez ◽

Mónica Esther Nambo-Arcos ◽

...

Keyword(s):

Synergistic Interactions ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential

Journal of Fungi ◽

10.3390/jof7020130 ◽

2021 ◽

Vol 7 (2) ◽

pp. 130

Author(s):

Nathan P. Wiederhold

Keyword(s):

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Candida Species ◽

Mammalian Cells ◽

Mitochondrial Membrane ◽

Fungal Infections ◽

Published Data ◽

Candida Auris

Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris, as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans, C. glabrata, and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available.

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Glycoside Hydrolases Degrade Polymicrobial Bacterial Biofilms in Wounds

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01998-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 43

Author(s):

Derek Fleming ◽

Laura Chahin ◽

Kendra Rumbaugh

Keyword(s):

Glycoside Hydrolase ◽

Bacterial Population ◽

Chronic Wounds ◽

Glycoside Hydrolases ◽

Bacterial Biofilms ◽

Planktonic Cells ◽

Content Type ◽

Biomass Dissolution

ABSTRACT The persistent nature of chronic wounds leaves them highly susceptible to invasion by a variety of pathogens that have the ability to construct an extracellular polymeric substance (EPS). This EPS makes the bacterial population, or biofilm, up to 1,000-fold more antibiotic tolerant than planktonic cells and makes wound healing extremely difficult. Thus, compounds which have the ability to degrade biofilms, but not host tissue components, are highly sought after for clinical applications. In this study, we examined the efficacy of two glycoside hydrolases, α-amylase and cellulase, which break down complex polysaccharides, to effectively disrupt Staphylococcus aureus and Pseudomonas aeruginosa monoculture and coculture biofilms. We hypothesized that glycoside hydrolase therapy would significantly reduce EPS biomass and convert bacteria to their planktonic state, leaving them more susceptible to conventional antimicrobials. Treatment of S. aureus and P. aeruginosa biofilms, grown in vitro and in vivo, with solutions of α-amylase and cellulase resulted in significant reductions in biomass, dissolution of the biofilm, and an increase in the effectiveness of subsequent antibiotic treatments. These data suggest that glycoside hydrolase therapy represents a potential safe, effective, and new avenue of treatment for biofilm-related infections.

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In Vitro Activities of Voriconazole in Combination with Three Other Antifungal Agents against Candida glabrata

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.9.3317-3322.2004 ◽

2004 ◽

Vol 48 (9) ◽

pp. 3317-3322 ◽

Cited By ~ 21

Author(s):

Francesco Barchiesi ◽

Elisabetta Spreghini ◽

Monia Maracci ◽

Annette W. Fothergill ◽

Isabella Baldassarri ◽

...

Keyword(s):

Candida Glabrata ◽

Antifungal Agents ◽

Beneficial Effects ◽

Synergistic Interactions ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Disk Diffusion Assay ◽

Combination Regimens

ABSTRACT Candida glabrata has recently emerged as a significant pathogen involved in both superficial and deep-seated infections. In the present study, a checkerboard broth microdilution method was performed to investigate the in vitro activities of voriconazole (VOR) in combination with terbinafine (TRB), amphotericin B (AMB), and flucytosine (5FC) against 20 clinical isolates of C. glabrata. Synergy, defined as a fractional inhibitory concentration (FIC) index of ≤0.50, was observed in 75% of VOR-TRB, 10% of VOR-AMB, and 5% of VOR-5FC interactions. None of these combinations yielded antagonistic interactions (FIC index > 4). When synergy was not achieved, there was still a decrease in the MIC of one or both drugs used in the combination. In particular, the MICs were reduced to ≤1.0 μg/ml as a result of the combination for all isolates for which the AMB MIC at the baseline was ≥2.0 μg/ml. By a disk diffusion assay, the halo diameters produced by antifungal agents in combination were greater that those produced by each drug alone. Finally, killing curves showed that VOR-AMB exhibited synergistic interactions, while VOR-5FC sustained fungicidal activities against C. glabrata. These studies demonstrate that the in vitro activity of VOR against this important yeast pathogen can be enhanced upon combination with other drugs that have different modes of action or that target a different step in the ergosterol pathway. Further studies are warranted to elucidate the potential beneficial effects of such combination regimens in vivo.

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1222. Are Reduced Concentrations of Chlorine-Based Disinfectants Effective Against Candida auris?

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1085 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S439-S439

Author(s):

Jessica Kumar ◽

Jennifer Cadnum ◽

Y Karen Ng Wong ◽

Thriveen Sankar Chittoor Mana ◽

Heba Alhmidi ◽

...

Keyword(s):

Sodium Hypochlorite ◽

Exposure Time ◽

Environmental Protection Agency ◽

Simulated Patient ◽

Patient Room ◽

Candida Auris ◽

Colony Forming Units ◽

Sodium Dichloroisocyanurate

Abstract Background Currently, sporicidal disinfectants such as bleach are recommended for daily and terminal disinfection of the rooms of patients with Candida auris colonization and/or infection. However, bleach and other chlorine-based disinfectants can have adverse effects on surfaces and personnel. Disinfectant solutions with reduced chlorine concentrations are commonly used for other pathogens, but it is not known if diluted or alternative products maintain efficacy against C. auris both in vitro and in vivo. Methods We tested the efficacy of different concentrations of a sodium dichloroisocyanurate (NaDCC) product and sodium hypochlorite using the method recommended by the Environmental Protection Agency (EPA) for evaluation of the efficacy of liquid disinfectants against C. auris (EPA MLB SOP MB-35-00) and in a simulated patient room. Carriers were exposed to each disinfectant for 1 and 2 minutes. Log reductions were calculated by subtracting viable organisms recovered after disinfectant exposure vs. deionized water controls. Results As shown in the figure, the NaDCC product at 4306 ppm tested with a 2 minute contact time reduced C. auris by ≥5 log10 colony-forming units (CFU) but had reduced efficacy with shorter exposure time or lower concentrations. Sodium hypochlorite was effective with 1 or 2 minute exposure times at a concentration of 6,500 ppm, and was effective at 4,000 ppm with an exposure time of 2 minutes. In the simulated patient room, NaDCC reduced C. auris contamination by ≥6 log10 CFUs on all surfaces. Conclusion A chlorine-based NaDCC product was effective at reducing C. auris. Both NaDCC and sodium hypochlorite products exhibited reduced efficacy at lower concentrations, particularly at concentrations below 4000 ppm. The NaDCC products were also effective in reducing contamination in the simulated patient room. UV-C treatment was an effective adjunct to manual cleaning. Disclosures All authors: No reported disclosures.

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The Fungal Cyp51-Specific Inhibitor VT-1598 DemonstratesIn VitroandIn VivoActivity againstCandida auris

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02233-18 ◽

2018 ◽

Vol 63 (3) ◽

Cited By ~ 10

Author(s):

Nathan P. Wiederhold ◽

Shawn R. Lockhart ◽

Laura K. Najvar ◽

Elizabeth L. Berkow ◽

Rosie Jaramillo ◽

...

Keyword(s):

Specific Inhibitor ◽

Candida Auris ◽

Once Daily ◽

Content Type ◽

Fungal Burden ◽

Invasive Infections ◽

Trough Concentrations ◽

Dose Dependent

ABSTRACTCandida aurisis an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluatedin vitroandin vivoagainstC. auris. Susceptibility testing was performed against 100 clinical isolates ofC. aurisby broth microdilution. Neutropenic mice were infected intravenously withC. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstratedin vitroactivity againstC. auris, with a mode MIC of 0.25 μg/ml and MICs ranging from 0.03 to 8 μg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused byC. auris.

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In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00306-21 ◽

2021 ◽

Author(s):

Janet Herrada ◽

Ahmed Gamal ◽

Lisa Long ◽

Sonia P. Sanchez ◽

Thomas S. McCormick ◽

...

Keyword(s):

Antifungal Activity ◽

Amphotericin B ◽

Kidney Tissue ◽

Treated Group ◽

Untreated Group ◽

Candida Auris ◽

Fungal Burden ◽

In Vivo Antifungal Activity

Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris in vitro as well as in vivo.

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