Efficacy And Safety Of Caspofungin Inhalations For Prevention And Treatment Of Invasive Pulmonary Aspergillosis In Mice

Invasive aspergillosis is a significant cause of morbidity and mortality in heavily immunocompromised patients and is associated with significant hospital costs and therapy complications in those with multiple comorbidities. Targeted pulmonary delivery by aerosolization of antifungals has recently gained attention, The use of aerosols for targeting medication to the receptor sites in the lung has multiple advantages compared to systemic administration, including the use of less drug to provide the same therapeutic effect and the reduction in the likelihood of systemic side effects.Our objective was to establish the mice model of IPA and assess the Efficacy and safety of caspofungin inhalations for prevention and treatment of invasive pulmonary aspergillosis in mice.Three parts of this research are as following: 1. Establishment of animal model of invasive pulmonary aspergillosis in immunosuppressed miceObjective Animal experiments are widely used in the diagnosis and treatment of invasive pulmonary aspergillosis (IPA). We establish an experimental model of IPA in neutropenic ICR mice with method of tracheal intubation.Methods Female ICR mice was immunosuppressed with cyclosphamide and Dexamethasone and inoculated with1×107conodia of Aspergillus fumigates.Patholigic examination were evaluated to determine whether the IPA model was successfully constructed. survival curves was draw,Fungal burden analysis following24h inoculation to compare these two methods.Results IPA was confirmed in neutropenic ICR mice with method of tracheal intubation based on pathologic examination. Mortality of mice was55%within7d after inculation,Numbers of CFU from homogenized lung tissues of IPA mice were5.17±0.32and3.82±0.49(log/gram lung) with these two methods of tracheal intubation and intranasal challenge, respectively.Conclusion The IPA model in immunosuppressed ICR mice is constructed successfully,and tracheal intubation was better than intranasal challenge.2. Efficacy of caspofungin inhalations for prevention and treatment of invasive pulmonary aspergillosis in miceObjective To evaluated the effectiveness of aerosolizing caspofungin as prophylaxis and treatment against invasive pulmonary aspergillosis caused by Aspergillus fumigates in an established model.Methods Immunocompromised ICR mice received either caspofungin by intraperitoneal injection or by aerosolization.dosing began2days prior or after pulmonary incoculation with A. fumigates and continued until7days after pulmonary incoculation. Survival and pulmonary fungal burden were assessed.Results The use of aerosolization of caspofungin,either as a prophylactic or therapeutic agent, is effective in reducing pulmonary fungal burden of immunosuppressed animals with pulmonary aspergillosis. But only caspofungin inhalations for prevention, is effective in reducing mortality of immunosuppressed animals.Conclusion Aerosol administration of caspofungin, especially used as prophylactic,could be an additional approach to optimizing treatment of invasive pulmonary aspergillosis.3. safety of caspofungin inhalations in miceObjective To evaluated the histologic effects, immunogenic potential after servel inhalations of caspofungin.Methods ICR mice received caspofungin by aerosolization dosing for1h/day(LD group),2h/day(HD group), or saline control for up to7days. Coronal sections of the entire lung were stained,viewed by light microscopy, and the histopathologic inflammatory score was obtained for each lobe. Cytokine induction of IL-1β、IL-6、TNF-α was assessed by Real-time PCR.Results The lung histopathologic scores for HD group, LD group, and saline control on days7did not differ between groups. Real-time PCR analysis showed no cytokine induction of IL-1β、IL-6、TNF-α.Conclusion Aerosol administration of caspofungin for up to7days do not apper to be immunogic and do not cause changes in pulmonary histology. Aerosolization of caspofungin is a safe method of pulmonary delivery.In conclusion, Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing caspofungin as prophylaxis and treatment against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled caspofungin significantly improved survival and limited the pulmonary fungal burden, as assessed by histopathology, compared to control and amphotericin B treatments. Inhalations were easy to administer and were well tolerated. This experience suggests The physiologic profile of the response to inhaled caspofungin is acceptable and is well tolerated. It merits further assessment in the treatment of pulmonary fungal disease.