WS04.1 Impaired mucus clearance promotes Aspergillus fumigatus-induced type 2 airway inflammation in cystic fibrosis-like lung disease in mice

Objectives: The polymicrobial nature in pulmonary infections in patients with CF is one the causes of the lack of efficacy of existing antibiotic treatment. The aim of the present study was to evaluate clinical efficacy of nebulized solution of novel antimicrobial drug candidate Mul-1867 (Poly-N,N′-hexamethyleneguanidine, modified by hydrazine) in murine pneumonia model caused by mixed infection. Methods: 8-weeks old C57BL/6 mice were intranasally infected with P. aeruginosa + S. aureus (each 1×105 cfu/mouse) or P. aeruginosa + C. albicans (each 1×105 cfu/mouse) mix. Treatment was started 12h after infection with Mul-1867 or Amikacin (taken as representative of aminoglycosides that are used for the treatment of lung infections in CF patients), both administered by intranasal inhalation at 32×MIC. Results: Mul-1867 exhibited a high level of antimicrobial activity with the MIC 0.25mg/L against S. aureus; 0.5mg/L against C. albicans and 4.0mg/L against P. aeruginosa. Amikacin was less active; the MICs 128mg/L for both S. aureus and P. aeruginosa and was not active against C. albicans. Induced pneumonia displayed a total death of control animals without of treatment within 72h post-infection in both groups with mixed infections. For the group P. aeruginosa + S. aureus treated with Mul-1867 to the end of observation period (72h) 20% of mice died. Only 10% animals died in P. aeruginosa + C. albicans group treated with Mul-1867. Animals treated with Amikacin displayed 50% mortality in P. aeruginosa + S. aureus group and 70% mortality in P. aeruginosa + C. albicans. Conclusion: Our study demonstrated that Mul-1867 possesses great activity against mixed infection, including bacterial–fungal mix.