Abstract
INTRODUCTION: N-chlorotaurine (NCT), a long-lived oxidant of human granulocytes, can be used topically as anti-infective in different body regions. The aim of the present study was to demonstrate the efficacy and tolerability of inhaled NCT in a mouse model of Aspergillus fumigatus pneumonia. METHODS: Specific pathogen-free female C57BL/6JRj mice were immune-suppressed with cyclophosphamide or cortisone acetate. After 7 days, they were inoculated intranasally with 6.5 × 106 spores of A. fumigatus. Treatment with aerosolized (<5 µm) aqueous 0.1%, 0.5%, 1.0%, or 2.0% NCT solution or 0.9% sodium chloride as placebo three times daily for 10 min was started 1 h after inoculation and ended after 14-16 days. Prophylactic treatment exclusively for 2 days before infection was investigated additionally. Main parameters of evaluation were survival and fungal load in the lung homogenate, secondary ones clinical (body weight, organ weights, body temperature) and blood inflammation parameters, bronchoalveolar lavage fluid analysis, and histology of organs. RESULTS: Pneumonia occurred in all mice, but the survival was much higher in animals treated with NCT compared to placebo. In placebo groups, 8/9 mice observed for 15 days died from the infection during this time, while 0/9 to 1/9 died in groups treated with 0.5%, 1.0%, and 2.0% NCT (p < 0.01 for each concentration versus saline). There was no difference between the two ways of immune-suppression. With 0.1% NCT, 4/9 mice died (p = 0.029 versus 0.5% and 2.0% NCT; p = 0.0035 versus control). The fungal load came to 5.28 log(10) (4.46; 5.70; median, quartiles) colony-forming units per ml lung homogenate in the control group and to 1.3 log(10) (median; maximum 2.45) in the 1% NCT group in mice immune-suppressed with cyclophosphamide (p = 0.0004). Values were similar in cortisone groups (p = 0.0023). Of note, the prophylactic inhalations with 1% NCT were equally effective. Loss of body weight was significantly higher in the control animals compared to the test ones. Organ weights of the lung, brain, and kidney were significantly higher in the control groups than in the test groups, while the opposite was found for the spleen weight with more lymphatic hyperplasia in the test animals. Mice treated with 2.0% NCT had a breath sound for a few minutes after inhalation, but no further hints for incompatibility or discomfort could be detected. CONCLUSION: Early treatment with inhaled NCT as well as prophylactic treatment demonstrated a highly significant beneficial efficacy in Aspergillus pneumonia. A concentration around 1% NCT appears to be optimal taking into account both tolerability and efficacy, which is in agreement with previous studies and case experiences in humans. Inhalation with NCT as an antiseptic and anti-infective product of granulocytes is highly promising in infections of the lower airways and should be further developed to achieve drug approval.