Aerosolization of Second-generation Triazoles: In Vitro Evaluation and Application in Therapy of Invasive Airway Aspergillosis

Abstract

Original Clinical Science -General Background. A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered. Methods. Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. Results. Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (<5.4 µm) of 2.8 µm, 2.0, 86%; 3.4 µm, 2.4, 78%; and 3.0 µm, 2.3, 79% for voriconazole and 6, 12 mg/mL of posaconazole, respectively. Aspergillus fumigatus isolate from the patient was more susceptible to voriconazole, and hence aerosolized voriconazole was introduced around the third month posttransplant at 40 mg TID for 1 week, 40 mg BID for 1 week, followed by 40 mg daily thereafter, along with IV caspofungin (50 mg/d) and liposomal amphotericin B (300 mg/d). The aerosol regimen was well tolerated by the patient with undetectable trough plasma levels of voriconazole. Bronchoscopy at the fourth month revealed improvement in anastomotic plaques with reduction in bronchoalveolar lavage galactomannan values (7.48-2.15 ng/mL). This consolidated aerosolized and intravenous regimen was maintained until 2.97 years posttransplant. Conclusions. The intravenous solutions of both second-generation triazoles showed characteristics that were suitable for aerosol delivery. Our report further adds to the therapeutic experience with the use of aerosolized voriconazole for IA in a lung transplant patient.

Inhaled Antifungal Agents for Treatment and Prophylaxis of Bronchopulmonary Invasive Mold Infections

“…Several studies have investigated the aerodynamic properties of nebulized voriconazole (n-VRZ) using commercially available solutions concentrated at 6.25 to 10 mg/mL. The MMAD was 2.4 to 2.98 μm and the FPF was 71.7–93.0% [ 131 , 132 , 133 , 134 ]. These results suggested an appropriate distribution of the nebulized droplets into the distal zones of the lung but a rapid systemic absorption.…”

“…In humans, four case reports have been reported thus far using n-VRZ as an adjunctive treatment of IMI (see Supplementary Table S7 ). Two publications involving three lung transplant recipients and one immunosuppressed patient with IPA showed clinical and/or radiological cure or improvement with n-VRZ 40 mg administered one to three times daily, alone or as adjunctive treatment [ 131 , 132 ]. n-VRZ 40 mg once or twice daily has also been used as an adjunctive treatment for Scedosporium apiospermum and Microascus sp.…”

“…The aerodynamic properties of nebulized molecules of IV posaconazole solutions have been characterized. With an MMAD of 3.0 to 3.4 µm and a FPF of 78–79% for solutions concentrated at 6 to 12 mg/mL, an appropriate distribution in the lungs is suggested [ 132 ]. Alhough posaconazole is a lipophilic molecule with a LogD of 2.15 at pH 7.4, it is not a good candidate for nebulization.…”

A Critical Review on Emerging Trends in Dry Powder Inhaler Formulation for the Treatment of Pulmonary Aspergillosis

“…Both aerosolized azoles possessed favourable aerodynamic properties with MMAD of 2.8 µm, FPF of 76.8% and GSD of 2.0 for aerosolized VRZ, where MMAD of 2.4 µm, FPF of 62.9% and GSD of 2.4 for aerosolized PCZ with lower concentration (6 mg/mL). Besides, both aerosolized azoles had high respirable fraction, which was less than 5.4 µm (>75%) indicating possible deposition in the peripheral airways of the lungs [69]. On the other hand, aerosolization of reconstituted 100 mg powder of Mycamine ® (micafungin) and Ecalta ® (anidulafungin) with 0.9% sodium chloride possessed suitable pH, osmolality, chloride content and density values, similar to the values of water.…”

Opportunist Coinfections by Nontuberculous Mycobacteria and Fungi in Immunocompromised Patients

“…Tests conducted in mice models with M. avium and M. abscessus showed promising results for clofazimine administered by inhalation [189]. The same option has been developed for pulmonary aspergillosis, where aerosolized delivery of liposomal amphotericin B, voriconazole or posaconazole is applicable [190,191]. Antimicrobial peptides exhibit a broad-spectrum of antimicrobial activity against bacteria, viruses, parasites and fungi, and could be alternatives for the treatment of mycobacterial infections [192].…”