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In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels

The in vitro/in vivo correlation of antifungal combination testing is necessary in order to assess the efficacy of combination regimens. We, therefore, attempted to correlate in vitro chequerboard testing of posaconazole (POS) and amphotericin B (AMB) with the in vivo outcome of combination therapy...

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Autores principales: Meletiadis, Joseph, Beredaki, Maria-Ioanna, Elefanti, Antigoni, Pournaras, Spyros, Muller, Anouk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10146624/
https://www.ncbi.nlm.nih.gov/pubmed/37108889
http://dx.doi.org/10.3390/jof9040434
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author Meletiadis, Joseph
Beredaki, Maria-Ioanna
Elefanti, Antigoni
Pournaras, Spyros
Muller, Anouk
author_facet Meletiadis, Joseph
Beredaki, Maria-Ioanna
Elefanti, Antigoni
Pournaras, Spyros
Muller, Anouk
author_sort Meletiadis, Joseph
collection PubMed
description The in vitro/in vivo correlation of antifungal combination testing is necessary in order to assess the efficacy of combination regimens. We, therefore, attempted to correlate in vitro chequerboard testing of posaconazole (POS) and amphotericin B (AMB) with the in vivo outcome of combination therapy against experimental candidiasis in a neutropenic murine model. The AMB + POS combination was tested against a Candida albicans isolate. In vitro, a broth microdilution 8 × 12 chequerboard method with serial two-fold drug dilutions was used. In vivo, CD1 female neutropenic mice with experimental disseminated candidiasis were treated with i.p. AMB and p.o. POS alone and in combination at three effective doses (ED20, ED50 and ED80 corresponding to 20%, 50% and 80% of maximal effect, respectively). CFU/kidneys after 2 days were determined. The pharmacodynamic interactions were assessed based on Bliss independence interaction analysis. In vitro, a Bliss antagonism of −23% (−23% to −22%) was observed at 0.03–0.125 mg/L of AMB with 0.004–0.015 mg/L of POS, while a Bliss synergy of 27% (14%–58%) was observed at 0.008–0.03 mg/L of AMB with 0.000015–0.001 mg/L of POS. In vivo, Bliss synergy (13 ± 4%) was found when an AMB ED20 of 1 mg/kg was combined with all POS ED 0.2–0.9 mg/kg, while Bliss antagonism (35–83%) was found for the combinations of AMB ED50 2 mg/kg and ED80 3.2 mg/kg with POS ED80 of 0.9 mg/kg. Free drug serum levels of POS and AMB in in vivo synergistic and antagonistic combinations were correlated with the in vitro synergistic and antagonistic concentrations, respectively. Both synergistic and antagonistic interactions were found for the AMB + POS combination. POS compromised the efficacy of high effective AMB doses and enhanced low ineffective AMB doses. In vitro concentration-dependent interactions were correlated with in vivo dose-dependent interactions of the AMB + POS combination. In vivo interactions occurred at free drug serum levels close to in vitro interacting concentrations.
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spelling pubmed-101466242023-04-29 In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels Meletiadis, Joseph Beredaki, Maria-Ioanna Elefanti, Antigoni Pournaras, Spyros Muller, Anouk J Fungi (Basel) Article The in vitro/in vivo correlation of antifungal combination testing is necessary in order to assess the efficacy of combination regimens. We, therefore, attempted to correlate in vitro chequerboard testing of posaconazole (POS) and amphotericin B (AMB) with the in vivo outcome of combination therapy against experimental candidiasis in a neutropenic murine model. The AMB + POS combination was tested against a Candida albicans isolate. In vitro, a broth microdilution 8 × 12 chequerboard method with serial two-fold drug dilutions was used. In vivo, CD1 female neutropenic mice with experimental disseminated candidiasis were treated with i.p. AMB and p.o. POS alone and in combination at three effective doses (ED20, ED50 and ED80 corresponding to 20%, 50% and 80% of maximal effect, respectively). CFU/kidneys after 2 days were determined. The pharmacodynamic interactions were assessed based on Bliss independence interaction analysis. In vitro, a Bliss antagonism of −23% (−23% to −22%) was observed at 0.03–0.125 mg/L of AMB with 0.004–0.015 mg/L of POS, while a Bliss synergy of 27% (14%–58%) was observed at 0.008–0.03 mg/L of AMB with 0.000015–0.001 mg/L of POS. In vivo, Bliss synergy (13 ± 4%) was found when an AMB ED20 of 1 mg/kg was combined with all POS ED 0.2–0.9 mg/kg, while Bliss antagonism (35–83%) was found for the combinations of AMB ED50 2 mg/kg and ED80 3.2 mg/kg with POS ED80 of 0.9 mg/kg. Free drug serum levels of POS and AMB in in vivo synergistic and antagonistic combinations were correlated with the in vitro synergistic and antagonistic concentrations, respectively. Both synergistic and antagonistic interactions were found for the AMB + POS combination. POS compromised the efficacy of high effective AMB doses and enhanced low ineffective AMB doses. In vitro concentration-dependent interactions were correlated with in vivo dose-dependent interactions of the AMB + POS combination. In vivo interactions occurred at free drug serum levels close to in vitro interacting concentrations. MDPI 2023-04-01 /pmc/articles/PMC10146624/ /pubmed/37108889 http://dx.doi.org/10.3390/jof9040434 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Meletiadis, Joseph
Beredaki, Maria-Ioanna
Elefanti, Antigoni
Pournaras, Spyros
Muller, Anouk
In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels
title In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels
title_full In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels
title_fullStr In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels
title_full_unstemmed In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels
title_short In Vitro–In Vivo Correlation of Posaconazole–Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels
title_sort in vitro–in vivo correlation of posaconazole–amphotericin b combination against candida albicans: in vitro interacting concentrations are associated with in vivo free drug levels
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10146624/
https://www.ncbi.nlm.nih.gov/pubmed/37108889
http://dx.doi.org/10.3390/jof9040434
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