Extended Spectrum Triazole Plus Type II Topoisomerase Inhibitor (TI) against Azole-Resistant (R) Isolates of Aspergillus: Synergistic Interaction in vitro

Ref ID: 15147

Author:

S. KRISHNAN-NATESAN, S. SWAMINATHAN, P. CHANDRASEKAR

Author address:

Wayne State Univ., Detroit, MI, 2John D. Dingell VA Med. Ctr., Detroit, MI.

Full conference title:

50th Annual ICAAC

Date: 12 September 2014

Abstract:

Background: The high mortality rate and emerging antifungal drug resistance associated with invasive aspergillosis emphasizes the need for novel, more potent fungicidal agents.TIs have not been evaluated against azole-R Aspergillus. Fungal topoisomerases differ from their mammalian counterparts. Aim: To investigate the efficacy of type II TIs (Ciprofloxacin-CIP; levofloxacin-LEV; moxifloxacin-MOX) plus VCZ or POS against VCZ-R A. flavus (n=10) and POS-R A. fumigatus (n=10) Methods: Fresh conidial suspensions were prepared from VCZ-R A. flavus and POS-R A fumigatus, (n= 20; MIC 2-16 mcg/ml). The in vitro susceptibility of Aspergillus to 2-drug combinations of VCZ or POS with CIP, LEV or MOX (0.125-32 mcg/ml) was evaluated using FICI (fractional inhibitory concentration index) and CLSI-M38-A2 method, followed by menadione-augmented MTT (Methyl-thiazolyl tetrazolium bromide) assay. The insoluble blue formazan salt produced by viable hyphae was dissolved in 95% isopropanol and quantitated by spectrophotometry (OD550). Drug interaction was defined as synergistic, no interaction or antagonistic if FICI< 0.5, 0.5-4 or > 4 respectively. Results: TIs alone had no activity (MIC > 512mcg/ml) against Aspergillus. CIP (2 mcg/ml) plus VCZ or POS (0.5-1 mcg/ml) demonstrated synergy against all isolates tested. FICI was < 0.5, < 0.5-1 and < 0.5-1 and reduction in OD550 (reduced formazan production by non-viable hyphae) was ≥ 80%, 60% and 60% for triazoles with CIP, LEV or MOX respectively; > 2-fold decrease in MIC-80 was noted for VCZ or POS with TIs; antagonism was observed with ≥ 128 mcg/ml of TIs. Conclusion: TI plus triazole showed synergy against azole-R Aspergillus. CIP had the best synergy among the 3 TIs studied. Triazoles likely increase fungal cell membrane permeability to TIs; TIs appear to have affinity to fungal topoisomerases and need to be further explored for their potential antifungal activity.

Abstract Number: M-396

Conference Year: 2010

Link to conference website: NULL

New link: NULL

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