Chemosensitizers As Therapeutic Adjuncts in Allergic Airway Disease

An L Nguyen, MD, Paul Porter, PhD, David B. Corry, MD

Abstract: 

Rationale:

Treatment with antifungal agents often improves clinical outcomes in patients with allergic airway disease and airway mycosis. However, antifungals are ineffective in some patients due to dose-limiting toxicity and fungal resistance. The purpose of this study was to identify adjunctive agents (chemosensitizers) that enhance the in vitro activity of antifungals against clinical mold isolates. 

Methods:

Molds were isolated from the sputum of patients with chronic rhinosinusitis or asthma who were seen at the Michael E. DeBakey VA Allergy Clinic. The MIC50 of itraconazole (I), voriconazole (V), and terbinafine (T) for each clinical isolate was determined by broth microdilution testing.  Antifungals and chemosensitizers were tested for synergy by dilution in a checkerboard microtiter plate format both alone and in combination, achieving physiological blood concentrations. Chemosensitizers used were cyclosporine and nifedipine. Fungal metabolic activity was determined using XTT reduction assay.

Results:

The MIC50 for clinical isolate sp314c2 for antifungals alone were 0.112(I), 0.168(V), and 0.098(T) ug/ml and were reduced to 0.029(I), 0.084(V), 0.020(T) ug/ml when tested in combination with the lowest tested dose of cyclosporine (0.31 ug/mL). This corresponds to a 3.94 (I), 2 (V), and 4.8 (T)-fold reduction in the MIC50. Testing with the lowest dose of nifedipine (0.08 ug/ml) led to a 3.99 (I), 1.37 (V), and 1.17 (T) fold reduction in the MIC50. 

Conclusions:

We have identified chemosensitizers that enhance antifungal activity against molds in vitro.  These agents may improve therapy of airway mycosis in patients who are intolerant of standard antifungal doses or have resistant organisms.

2017

abstract No: 

24

Full conference title: 

The American Academy of Allergy, Asthma & Immunology 2017
    • AAAAI 2017 (73rd)