Multilaboratory Testing of Two-Drug Combinations of Antifungals against
 Candida albicans
 ,
 Candida glabrata
 , and
 Candida parapsilosis

Chaturvedi, Vishnu; Ramani, Rama; Andes, David R.; Diekema, Daniel J.; Pfaller, Michael A.; Ghannoum, Mahmoud A.; Knapp, C C; Lockhart, Shawn R.; Ostrosky-Zeichner, Luis; Walsh, Thomas J.; Marchillo, Karen; Messer, S. A.; Welshenbaugh, A.; Bastulli, C. M.; Iqbal, Noreen; Paetznick, Victor L.; Rodríguez, José R.; Sein, Tin

doi:10.1128/aac.01510-09

Cited by 44 publications

(41 citation statements)

References 47 publications

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“…Each drug alone had very low MIC values for these strains, but they increased following the association, although still remaining low. With regard to echinocandins, most authors found no antagonism between micafungin and azoles or AMB (4,17,32). Barchiesi et al did not find advantages in associating caspofungin and the polyene, with the exception of C. parapsilosis, but the study in- cluded a much more limited number of strains (2).…”

Section: Discussionmentioning

confidence: 86%

“…The evaluation of in vitro drug interactions by FC was determined according to the staining index (SI), which is similar to the FICI described above. The SI was calculated as the sum of the percentage of depolarized cells (DC) after treatment with drug combinations divided by the DC of the drug alone for DiBAC 4 of the checkerboard results, an association provided by FC was defined as antagonism for SI of Ͻ1, no interaction for SI between 1 and 4, and synergy for an SI of Ͼ4.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Novel Method for Evaluating In Vitro Activity of Anidulafungin in Combination with Amphotericin B or Azoles

et al. 2012

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A combination of drugs possessing different targets has been used as salvage therapy, although without scientific support. In vitro studies validating such combinations are scarce, and the methodology is very laborious and time-consuming. This study proposes a flow cytometric (FC) protocol as an alternative to evaluate the effect of the combination of anidulafungin (AND) with amphotericin B (AMB) and azoles (fluconazole and voriconazole), tested upon 39 and 36 Candida strains, respectively. The concentration assayed in the combination was 0.5× MIC of each drug. The membrane potential marker DiBAC 4 (3) [Bis-(1,3-dibutylbarbituric acid) trimethine oxonol] was used for AND-AMB, and the metabolic marker FUN-1 was used for AND-azoles. Drug interaction was determined by calculating a staining index (SI): the sum of the percentage of depolarized cells (DC) after treatment with drug combinations divided by the DC of the drug alone, and the sum of the mean intensity of fluorescence (MIF) displayed by cells treated with drug combinations divided by the MIF of the drug alone for FUN-1. An SI of <1 means antagonism, an SI between 1 and 4 means no interaction, and an SI of >4 means synergism. The combination of AND and AMB by FC and checkerboard was synergistic for 46 and 43% of isolates and antagonistic for 5 and 8%, respectively. For the combination of AND and azoles, it was synergistic for 36% and antagonistic for 3% by FC and synergistic for 44% and antagonistic for 3% by checkerboard. When the FC method was compared to the gold standard checkerboard method, the agreement was 0.91 (95% confidence interval [95% CI] of 0.88 to 0.94), sensitivity was 0.88 (95% CI of 0.73 to 0.95), and specificity was 0.95 (95% CI of 0.84 to 1). Thus, FC is a rapid and reliable method (<2 h) to assess the effect of antifungal combinations.

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Section: Discussionmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Novel Method for Evaluating In Vitro Activity of Anidulafungin in Combination with Amphotericin B or Azoles

et al. 2012

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“…Regarding the effect of echinocandins on voriconazole inhibition zones when the three echinocandins (at 1, 6, and 12 mg/liter) were combined with voriconazole (at 0.5, 2, and 6 mg/liter) in spiked human serum, there was no difference between the inhibition zones of voriconazole alone and in the presence of each echinocandin (ANOVA P Ͼ 0.18). No interaction between voriconazole and echinocandins against C. parapsilosis isolates has been reported (29)(30)(31).…”

Section: Isolatementioning

confidence: 99%

Bioassay for Determining Voriconazole Serum Levels in Patients Receiving Combination Therapy with Echinocandins

Siopi

Neroutsos

Zisaki

et al. 2016

Antimicrob Agents Chemother

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Voriconazole is characterized by nonlinear pharmacokinetics due to saturation of its metabolism, resulting in unpredictable exposure with standard dosing regimens. Furthermore, it exhibits substantial inter-and intrapatient variability (88 to 100%), as many physiological, pathological, and pharmacological variables affect its serum concentrations (1). A correlation between serum concentrations and toxicity or response has been reported (2), whereas the benefit of therapeutic-drug monitoring (TDM) of voriconazole in the clinical setting has been demonstrated in many clinical studies, including a randomized clinical trial (3-7). Therefore, TDM of voriconazole is an important tool in individualized therapy, leading to dosage optimization in order to maximize the therapeutic effect and minimize toxicity.The clinical use and value of TDM are related to accurate, rapid, and cost-effective assays. Specifically, voriconazole levels in body fluids are often determined by using chromatographic or microbiological methods. Although high-performance liquid chromatography (HPLC) is still considered the gold standard, bioassays are frequently adopted and routinely performed because of their relative technical simplicity and low consumable and equipment costs, while there are several data indicating the concordance of results between the two methods (8-13). Nevertheless, current microbiological assays are lacking specificity in cases of antifungal combination therapy, as they do not allow the separation and simultaneous quantification of each individual compound. In light of the recent encouraging data from a large prospective randomized clinical trial on antifungal combination therapy (14), voriconazole may be combined with echinocandins in order to increase efficacy and overcome the limitations of voriconazole monotherapy, such as the long time to reach steady state, subtherapeutic levels, and difficult-to-treat infections (e.g., central nervous system [CNS] infections and those caused by azoleresistant pathogens) (15, 16). We therefore developed and validated an agar diffusion bioassay to determine voriconazole concentrations in the serum samples from patients on combination therapy with echinocandins.

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“…Unfortunately, high costs and serious side effects have put limitation on the combinations of antifungal drugs 12,13 . In addition, contradictory results of the synergistic or antagonistic action of various antifungals combination have been reported 9,14,15 . FLC-like drugs inhibit the cytochrome P450 sterol 14a-demethylase (14DM, CYP51) by coordinating the heme iron atom in the catalytic site with the azole nitrogen atom (N-3 and N-4 in the case of imidazole and triazole respectively).…”

Section: Introductionmentioning

confidence: 99%

Exploring the thiazole scaffold for the identification of new agents for the treatment of fluconazole resistant Candida

Meleddu

Distinto

Corona

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cyclohexyliden-and 2-methylcyclohexyliden-hydrazo-4-arylthiazoles were synthesized and tested as antifungal agents. All compounds exhibited minimal inhibitory concentration (MIC) values comparable with those of fluconazole (FLC). Moreover, some compounds showed fungicidal activity at low concentration. Worth noting five out of nine compounds were active towards Candida albicans 25 FLC resistant isolated from clinical specimens. The cellular toxicity was evaluated and none of the compounds is toxic at the MIC. On the basis of our data we can conclude that these derivatives are promising agents for the treatment of resistant C. albicans.

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Multilaboratory Testing of Two-Drug Combinations of Antifungals against Candida albicans , Candida glabrata , and Candida parapsilosis

Abstract: Median ⌺FIC values showed a wide dispersion, and interlaboratory agreements were less than 85% in most instances. Additional studies are needed to improve the interlaboratory reproducibility of antifungal combination testing.

Cited by 44 publications

References 47 publications

Novel Method for Evaluating In Vitro Activity of Anidulafungin in Combination with Amphotericin B or Azoles

Novel Method for Evaluating In Vitro Activity of Anidulafungin in Combination with Amphotericin B or Azoles

Bioassay for Determining Voriconazole Serum Levels in Patients Receiving Combination Therapy with Echinocandins

Exploring the thiazole scaffold for the identification of new agents for the treatment of fluconazole resistant Candida

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