Document Detail


Polyhexamethylene biguanide and calcineurin inhibitors as novel antifungal treatments for Aspergillus keratitis.
MedLine Citation:
PMID:  21849421     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: To establish polyhexamethylene biguanide (PHMB) as an effective treatment for Aspergillus keratitis in a novel murine model. To determine the ability of the calcineurin inhibitors tacrolimus (FK506) and cyclosporine A (CSA) to enhance the activity of PHMB, amphotericin B (AMB), and voriconazole (VCZ) against Aspergillus keratitis.
METHODS: In vitro studies: Broth antifungal susceptibility tests were performed with PHMB, AMB, VCZ, and FK506, individually and in combination against Aspergillus fumigatus. Minimum inhibitory concentrations (MIC) and fractional inhibitory concentration index (FICI) values were used to analyze antifungal activity. In vivo studies: A novel murine model was created to establish Aspergillus keratitis. Infected mice were randomly assigned to treatment groups receiving saline, CSA, AMB, VCZ, PHMB, AMB+CSA, VCZ+CSA, or PHMB+CSA. An ophthalmologist blinded to the treatment groups assessed disease severity daily based on a grading scale. The mean end change in disease score was compared between groups.
RESULTS: In vitro studies: FK506 in combination with PHMB, VCZ, or AMB enhanced fungal growth inhibition. FICI values showed an additive effect between FK506 and PHMB, AMB, or VCZ. PHMB monotherapy eliminated Aspergillus growth starting at 4 μg/mL. In vivo studies: All treatment groups showed a significant improvement in disease score compared to the control group. CSA significantly worsened VCZ activity against Aspergillus keratitis.
CONCLUSIONS: PHMB is an effective inhibitor of Aspergillus growth. Further investigation of the role of calcineurin inhibitors in the treatment for Aspergillus keratitis is warranted.
Authors:
Rachelle A Rebong; Ricardo M Santaella; Brian E Goldhagen; Christopher P Majka; John R Perfect; William J Steinbach; Natalie A Afshari
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-09-21
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  52     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-28     Completed Date:  2011-12-01     Revised Date:  2013-01-09    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7309-15     Citation Subset:  IM    
Affiliation:
Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Amphotericin B / pharmacology
Animals
Aspergillosis / drug therapy*,  microbiology
Aspergillus fumigatus / drug effects*
Biguanides / pharmacology,  therapeutic use*
Calcineurin / antagonists & inhibitors*
Corneal Ulcer / drug therapy*,  microbiology
Cyclosporine / pharmacology,  therapeutic use
Disinfectants / pharmacology,  therapeutic use
Drug Synergism
Eye Infections, Fungal / drug therapy*,  microbiology
Immunosuppressive Agents / pharmacology,  therapeutic use*
Male
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Prospective Studies
Pyrimidines / pharmacology
Tacrolimus / pharmacology
Triazoles / pharmacology
Chemical
Reg. No./Substance:
0/Biguanides; 0/Disinfectants; 0/Immunosuppressive Agents; 0/Pyrimidines; 0/Triazoles; 0/voriconazole; 109581-93-3/Tacrolimus; 1397-89-3/Amphotericin B; 28757-47-3/polyhexamethylene biguanide; 59865-13-3/Cyclosporine; EC 3.1.3.16/Calcineurin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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