Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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In vitro Interaction of Voriconazole Combined with Anidulafungin against Triazole Resistant Aspergillus fumigatus
Seyedmojtaba Seyedmousavi 1,2, Joseph Meletiadis 3, Willem J.G. Melchers 1,2, Antonius J.M.M. Rijs 1,2, Johan W. Mouton 1,2 and Paul E. Verweij 1,2,1,*
Author Affiliations: <SUP>1</SUP>Department of Medical Microbiology, Radboud University Nijmegen Medical centre, Nijmegen, the Netherlands; <SUP>2</SUP>Nijmegen Institute for Infection, Inflammation and Immunity, Nijmegen, the Netherlands; <SUP>3</SUP>Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
ABSTRACT
Voriconazole is the recommended drug of first choice to treat infections caused by Aspergillus fumigatus. The efficacy of voriconazole might be hampered by emergence of azole resistance. However, the combination of voriconazole with anidulafungin could improve therapeutic outcome in azole resistant invasive aspergillosis (IA). In vitro interaction between voriconazole and anidulafungin was determined against voriconazole-susceptible and voriconazole-resistant (substitutions in the cyp51A-gene: single point (M220I and G54W) and tandem repeat mutations (TR<SUB>34</SUB>/L98H and TR<SUB>46</SUB>/Y121F/T289A) ) clinical A.fumigatus isolates using a checkerboard microdilution method with spectrophotometric analysis and a viability-based XTT assay within 2 h of exposure after 24 and 48 h of incubation at 35?37?c. Fractional inhibitory concentration indices (FICis) were determined using different MIC endpoints and Bliss independence analysis performed based on response surface calculation of drugs no-interaction. Significant synergistic interactions obtained based on measuring FIC index were dependent of the MIC endpoint, in which FICs were inversely related with voriconazole and anidulafungin MICs and were influenced by CYP51A genotype. A statistically significant difference was observed between FIC indexes of isolates harboring tandem repeat mutations and wild type controls (one-way analysis of variance (ANOVA), P= 0.006), indicating that synergy is decreased in azole-resistant strains. Our results indicated that a combination of voriconazole and anidulafungin might be effective against infections caused by both azole-susceptible and azole-resistant A.fumigatus isolates, but the combination could possibly be less effective in voriconazole-resistant strains with high MICs. Studies in vivo and in vitro-in vivo correlation investigations are required to validate potential synergy of voriconazole and anidulafungin.
FOOTNOTES
*CORRESPONDING AUTHOR: Prof. Dr. Paul. E. Verweij, MD, PhD, Mailing address: Department of Medical Microbiology, Radboud University Nijmegen Medical centre, P.O.Box.9101, 6525HB Nijmegen, the Netherlands Phone: (31)243614356. Fax: (31)243540216. E-mail: P.Verweij@mmb.umcn.nl
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Seyedmojtaba Seyedmousavi 1,2, Joseph Meletiadis 3, Willem J.G. Melchers 1,2, Antonius J.M.M. Rijs 1,2, Johan W. Mouton 1,2 and Paul E. Verweij 1,2,1,*
Author Affiliations: <SUP>1</SUP>Department of Medical Microbiology, Radboud University Nijmegen Medical centre, Nijmegen, the Netherlands; <SUP>2</SUP>Nijmegen Institute for Infection, Inflammation and Immunity, Nijmegen, the Netherlands; <SUP>3</SUP>Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
ABSTRACT
Voriconazole is the recommended drug of first choice to treat infections caused by Aspergillus fumigatus. The efficacy of voriconazole might be hampered by emergence of azole resistance. However, the combination of voriconazole with anidulafungin could improve therapeutic outcome in azole resistant invasive aspergillosis (IA). In vitro interaction between voriconazole and anidulafungin was determined against voriconazole-susceptible and voriconazole-resistant (substitutions in the cyp51A-gene: single point (M220I and G54W) and tandem repeat mutations (TR<SUB>34</SUB>/L98H and TR<SUB>46</SUB>/Y121F/T289A) ) clinical A.fumigatus isolates using a checkerboard microdilution method with spectrophotometric analysis and a viability-based XTT assay within 2 h of exposure after 24 and 48 h of incubation at 35?37?c. Fractional inhibitory concentration indices (FICis) were determined using different MIC endpoints and Bliss independence analysis performed based on response surface calculation of drugs no-interaction. Significant synergistic interactions obtained based on measuring FIC index were dependent of the MIC endpoint, in which FICs were inversely related with voriconazole and anidulafungin MICs and were influenced by CYP51A genotype. A statistically significant difference was observed between FIC indexes of isolates harboring tandem repeat mutations and wild type controls (one-way analysis of variance (ANOVA), P= 0.006), indicating that synergy is decreased in azole-resistant strains. Our results indicated that a combination of voriconazole and anidulafungin might be effective against infections caused by both azole-susceptible and azole-resistant A.fumigatus isolates, but the combination could possibly be less effective in voriconazole-resistant strains with high MICs. Studies in vivo and in vitro-in vivo correlation investigations are required to validate potential synergy of voriconazole and anidulafungin.
FOOTNOTES
*CORRESPONDING AUTHOR: Prof. Dr. Paul. E. Verweij, MD, PhD, Mailing address: Department of Medical Microbiology, Radboud University Nijmegen Medical centre, P.O.Box.9101, 6525HB Nijmegen, the Netherlands Phone: (31)243614356. Fax: (31)243540216. E-mail: P.Verweij@mmb.umcn.nl
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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