CaspoNEB: Efficacy and Safety of Caspofungin Aerosols for the Curative Treatment of Pneumocystis Pneumonia

Pneumocystis Infections, Pneumocystis Jirovecii Infection, Pneumocystis Pneumonia

ventilation, Pneumocystis, caspofungin, echinocandin, aerosol, inhalation, nebulization, interstitial pneumonia

To assess the efficacy of administrating daily caspofungin aerosols versus placebo for seven days, in adjunction of conventional systemic antifungal therapy during curative treatment of Pneumocystis pneumonia, on the clinical outcome at the end of the nebulized therapy, in order to support a GO / NO GO decision towards a phase III trial of nebulized caspofungin in those patients.

Pneumocystis jirovecii is an airborne-transmissible fungus which can induce pneumonia with severely impaired lung function, especially in immunocompromised patients. At least 1,000 new cases of Pneumocystis pneumonia occur each year in France with approximately 50% of cases suffering from hypoxemia. Around 15% HIV+ and 50% HIV- subjects require mechanical ventilation, and mean duration of hospitalization is about 30 days. Average mortality rate is ≈20% at 3 months, higher for critically ill patients (30%-60%). To date, cotrimoxazole represents the gold standard anti-Pneumocystis treatment commonly associated with systemic corticosteroids in case of moderate-to-severe infection. However, treatment is long (several weeks) to achieve clearance of the fungus, which might favor lung sequelae like persistent inflammation or post-infectious fibrosis. Furthermore, therapeutic failures have been reported as high as 9-44% of patients. Five other drugs have been commonly used as curative alternatives to cotrimoxazole against P. jirovecii: pentamidine, primaquine + clindamycin, dapsone and atovaquone. Some are responsible for serious side effects, while others are complex to administer or less efficient. All exhibit clinically important drug-drug interactions. Therefore, in such a context, it is important to test new drugs and/or alternative delivery routes for existing therapies. Echinocandin drugs, including caspofungin, are usually administered daily to treat invasive candidiasis and aspergillosis. They target the fungal cell wall, thus inhibiting the β-(1,3)-D glucan synthase enzyme. Intravenous (IV) echinocandins are generally well tolerated and are not responsibles for major drug-drug interactions. IV caspofungin was also proven effective in animal models of Pneumocystis infection and significantly improve the overall survival. Two human studies showed that in-hospital and 3-month mortality rates were similar between patients receiving daily IV echinocandin and those receiving co-trimoxazole alone. Several case reports also showed 47 successful outcomes with IV caspofungin, alone or in combination with standard treatment. A recent study reported better response and lower in-hospital mortality in patients receiving the combination of cotrimoxazole + IV caspofungin with no severe adverse events. Therefore, IV echinocandins are now recommended in the European therapeutic guidelines for non-HIV patients as a salvage therapy (CII-grade) in association with co-trimoxazole. However, high molecular weight and elevated protein binding hamper optimal diffusion of IV caspofungin towards the lung alveoli (\<5% plasma concentration), where P. jirovecii thrives. Administration through an aerosol directly delivered into the lung may circumvent this limitation. Technical feasibility of echinocandin nebulization was demonstrated in vitro with several commercial nebulizers that provided aerosol particles with adequat size and pH to ensure lung tolerance. In vivo, nebulized caspofungin, at a dosage equivalent to the usual IV dosage, showed an excellent safety profile in rats. It also reduced the fungal burden by -99% and induced elevated and prolonged concentrations of the drug in the lungs (almost 50% of the total amounts of caspofungin initially deposited into the lungs of infected rats were still detectable at 48 hours) - largely above the usual minimal inhibitory concentrations of fungal pathogens -, while caspofungin detection was almost null in other organs and blood. Therefore, we hypothesize herein the therapeutic interest of caspofungin aerosols in adjunction with conventional antifungal therapy, as first-line curative treatment, to enhance the clinical recovery and to reduce the morbidity due to Pneumocystis pneumonia. As no clinical trials have been worldwide initiated, human efficacy and safety data of nebulized caspofungin are still lacking and will be first investigated in this study in patients. Thus organized in two successive parts, this phase I/II clinical trial represents a mandatory prelude for this original administration modality of caspofungin.

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