title: In vitro combinations of natamycin with voriconazole, itraconazole and micafungin against clinical Fusarium strains causing keratitis.
abstract: OBJECTIVE
  Fusarium species cause a broad spectrum of infections, from superficial to disseminated disease. Because Fusarium species are intrinsically resistant to most antifungal drugs, new approaches are needed. The aim of the present study was to evaluate the in vitro combination of natamycin with currently used antifungal drugs.
  
  
  METHODS
  The in vitro interactions of combinations between natamycin and voriconazole, itraconazole and micafungin applied to 20 clinical Fusarium strains (members of Fusarium falciforme, Fusarium napiforme, Fusarium petroliphilum, Fusarium proliferatum, Fusarium pseudensiforme and Fusarium sacchari) were evaluated using a chequerboard microdilution method. The MICs of all drugs alone and in combination were determined visually after 48 h and interactions were assessed using fractional inhibitory concentration index (FICI) analysis.
  
  
  RESULTS
  MICs of voriconazole and natamycin alone were 4 to >16 and 4-8 mg/L, respectively. Values were reduced 3.5-10-fold to 0.02-0.5 mg/L and 0.5-5-fold to 0.13-2 mg/L in combination, for the currently used antifungals and natamycin, respectively, demonstrating additive to synergistic interactions. The combinations natamycin/voriconazole, natamycin/itraconazole and natamycin/micafungin were synergistic (FICI ≤0.5) for 70%, 15% and 5% of the strains, respectively. No antagonism was found.
  
  
  CONCLUSIONS
  The combination of natamycin with voriconazole was strongly synergistic at clinically achievable serum concentrations.
authors.affiliation: CBS-KNAW Fungal Biodiversity Centre, PO Box 85167, 3508 AD Utrecht, The Netherlands Institutes of Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands Directorate General of Health Services, Ibri Hospital, Ministry of Health, Muscat, Oman a.alhatmi@cbs.knaw.nl.
authors.forename: Abdullah M S
authors.initials: AM
authors.lastname: Al-Hatmi
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Curfs-Breuker
authors.affiliation: Hospital General de México, O.D, Mexico City, Mexico.
authors.forename: Alexandro
authors.initials: A
authors.lastname: Bonifaz
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jacques F
authors.initials: JF
authors.lastname: Meis
authors.affiliation: CBS-KNAW Fungal Biodiversity Centre, PO Box 85167, 3508 AD Utrecht, The Netherlands Institutes of Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands Basic Pathology Department, Federal University of Paraná State, Curitiba, Paraná, Brazil Biology Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: G Sybren
authors.initials: GS
authors.lastname: De Hoog
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D003881:Dermatomycoses / Q000188:drug therapy* / Q000382:microbiology*; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology; D060585:Fusariosis / Q000188:drug therapy* / Q000382:microbiology*; D005670:Fusarium / Q000187:drug effects*; D017964:Itraconazole / Q000494:pharmacology; D007634:Keratitis / Q000188:drug therapy* / Q000382:microbiology*; D055666:Lipopeptides / Q000494:pharmacology; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D054714:Echinocandins; D055666:Lipopeptides; D017964:Itraconazole; D065819:Voriconazole; D000077551:Micafungin