Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model

Lignell, Anders; Löwdin, Elisabeth; Cars, Otto; Sjölin, Jan

doi:10.1093/jac/dkn154

Cited by 5 publications

(9 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, it was shown that, when the concentration of voriconazole had fallen below the MIC or when voriconazole was washed away, amphotericin B regained its fungicidal effect (13). In the strains of C. albicans resistant to voriconazole and those of C. glabrata and C. krusei with various susceptibilities to voriconazole investigated in the present study, exposure to voriconazole followed by amphotericin B resulted in reduced activity of amphotericin B in all but one strain.…”

Section: Discussionmentioning

confidence: 46%

“…This finding suggests that the voriconazole inhibitory effect might be sustained in some isolates. The reason for not recovering the fungicidal activity of amphotericin B after voriconazole exposure despite repeated doses of amphotericin B at 48 h and 72 h in any of the strains is difficult to explain but has also been seen in a previous study (13). It seems unlikely that this phenomenon is caused by voriconazole because of the gradually decreasing voriconazole concentration, which at the time of these amphotericin B exposures should be extremely low.…”

Section: Discussionmentioning

confidence: 80%

“…We have previously shown that voriconazole reduced the amphotericin B activity in C. albicans strains fully susceptible to voriconazole (12,13). Moreover, it was shown that, when the concentration of voriconazole had fallen below the MIC or when voriconazole was washed away, amphotericin B regained its fungicidal effect (13).…”

Section: Discussionmentioning

confidence: 99%

“…This model has been used to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B against Candida albicans (12,13). These studies investigated C. albicans strains fully susceptible to voriconazole.…”

mentioning

confidence: 99%

“…Computer software (ARUComb 1.5; Snowfall Communications, Uppsala, Sweden) was applied for programming the pump to infuse the drug at an exponentially decreasing rate. Pharmacokinetic analysis of the maximum drug concentrations in serum (C max ), minimum drug concentrations in serum (C min ), and t 1/2 s of regimens with voriconazole and amphotericin B has previously shown results close to target values (13). The in vitro model was placed in a thermostatic room at 35°C during the experiments.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in Candida Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone

Lignell

Löwdin

Cars

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazoledependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, ؊0.19; P ‫؍‬ 0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.Combination antifungal therapy may be one method to improve outcome in invasive Candida infections. Because animal model pharmacodynamic studies may have difficulties in simulating human pharmacokinetics, in vitro pharmacodynamic studies with simulated human pharmacokinetics represent an additional tool in the study of antifungal combinations in that they can yield data on drug-specific antifungal activities that will be of interest before initiating clinical trials.Recently, an in vitro kinetic model for the study of combination treatment with drugs having different elimination rates has been presented and validated (12). This model has been used to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B against Candida albicans (12, 13). These studies investigated C. albicans strains fully susceptible to voriconazole. The postulated mechanism is that inhibition of ergosterol synthesis leads to decrease of ergosterol content and thus diminishes the effect of amphotericin B, which uses this sterol to mediate its inhibitory effect. Consequently, it is reasonable to hypothesize that voriconazole-induced inhibition of the fungicidal activity of amphotericin B will not be observed in voriconazole-resistant stra...

show abstract

Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in Candida Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone

Lignell

Löwdin

Cars

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

Betamethasone augments the antifungal effect of menadione—towards a novel anti‐Candida albicans combination therapy

Jakab

Emri

Sipos

et al. 2015

J. Basic Microbiol.

View full text Add to dashboard Cite

The fluorinated glucocorticoid betamethasone stimulated both the extracellular phospholipase production and hypha formation of the opportunistic human pathogen Candida albicans and also decreased the efficiency of the polyene antimycotics amphotericin B and nystatin against C. albicans in a dose-dependent manner. Importantly, betamethasone increased synergistically the anti-Candida activity of the oxidative stress generating agent menadione, which may be exploited in future combination therapies to prevent or cure C. albicans infections, in the field of dermatology.

show abstract

Use of posaconazole in the treatment of invasive fungal infections

Mehta

Langston

2009

Expert Review of Hematology

View full text Add to dashboard Cite

The emergence of invasive fungal infections as an increasingly important clinical problem in immunocompromised patients highlights the need for more effective antifungal agents and better strategies for prevention, diagnosis and treatment. Posaconazole is an extended-spectrum triazole with broad activity against a variety of fungal pathogens, both yeasts and molds. In particular, it has activity against several emerging pathogens, such as the Zygomycetes, which are resistant to many currently available antifungals, making it an attractive agent for use in both prophylactic and therapeutic situations. Studies demonstrating the prophylactic utility of posaconazole in neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome, and in patients with graft-versus-host disease following allogeneic stem cell transplantation has led to the approval of the drug in the USA. These data have been reviewed elsewhere in detail. Published data on posaconazole as primary antifungal therapy are very limited, although there is a considerable amount of experience with the drug in the salvage setting following failure of or intolerance to other antifungal agents. In this review we will focus on the use of posaconazole for treatment of established invasive fungal infections, with a focus on opportunistic infections in immunocompromised patients.

show abstract

Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model

Abstract: Voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.

Cited by 5 publications

References 23 publications

Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in Candida Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone

Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in Candida Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone

Betamethasone augments the antifungal effect of menadione—towards a novel anti‐Candida albicans combination therapy

Use of posaconazole in the treatment of invasive fungal infections

Contact Info

Product

Resources

About