Successful salvage therapy for fungal bronchial anastomotic infection after –lung transplantation with an inhaled triazole anti-fungal PC945

Fungal bronchial anastomotic infection owing to Aspergillus fumigatus is a devastating complication of lung transplantation (LT) that may result in bronchial dehiscence, bronchopleural fistula, or fatal hemorrhage.1Husain S Mooney ML Danziger-Isakov L et al.A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients.J Heart Lung Transplant. 2011; 30: 361-374Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Endobronchial infection at the anastomotic site is believed to result from poor vascularization and impaired host defense mechanisms, fostering local fungal invasion.2Santacruz JF Mehta AC Airway complications and management after lung transplantation: ischemia, dehiscence, and stenosis.Proc Am Thorac Soc. 2009; 6: 79-93Crossref PubMed Scopus (176) Google Scholar,3Hsu JL Manouvakhova OV Clemons KV et al.Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation.Sci Transl Med. 2018; 10: eaag2616Crossref PubMed Scopus (19) Google Scholar Treatment response to systemic anti-fungal agents is unpredictable because of poor local penetration, systemic toxicity, and pharmacokinetic variability. This is the report of the use of PC945 (Pulmocide), a potent inhaled triazole agent, to treat invasive Aspergillus infection of the respiratory tract under a Special Needs program, regulated within the United Kingdom by the Medicines and Health Care Products Regulatory Agency. PC945 shows potent in vitro anti-fungal activity against Aspergillus species, including itraconazole-resistant strains of Aspergillus fumigatus, Candida albicans, C glabrata, C krusei, C auris, Cryptococcus spp., and Rhizopus oryzae. A 29-year-old woman with cystic fibrosis (Patient 1) developed pneumonia 4 weeks post-LT. A. fumigatus complex, sensitive to itraconazole, voriconazole, echinocandins, and amphotericin B, and strongly positive galactomannan were found on bronchoalveolar lavage. She received caspofungin; isavuconazole, replaced by posaconazole because of gastroenteric intolerance; and nebulized amphotericin B deoxycholate (AmpBD) 25 mg twice daily. Follow-up bronchoscopies revealed a hyphal mass entwined with bronchial sutures despite 4 weeks of treatment. Despite addition of terbinafine, the mass increased over a 6-week period (Figure 1a). Biopsy confirmed fungal hyphae infiltrating the cartilage. Owing to disease progression, nebulized PC945 5 mg once daily was instituted in place of AmpBD. Serial bronchoscopy showed improvement after 2 weeks and complete dissolution after 8 weeks (Figure 1b and c). She received PC945 for 3 months and remains free from infection 3 months after completion, while continuing posaconazole and terbinafine. A 47-year-old man (Patient 2) underwent LT for alpha1-antitripsin deficiency. Three months post-LT, a left anastomotic fungal mass developed with a cavity underneath, which progressed despite ongoing treatment with caspofungin and nebulized AmpBD. The bronchoalveolar lavage grew A. fumigatus complex sensitive to itraconazole, voriconazole, echinocandins, and amphotericin B, and galactomannan was strongly positive. Oral posaconazole and terbinafine were added without benefit after 3 weeks at therapeutic plasma levels (Figure 1d). Nebulized AmpBD was replaced by PC945 (5 mg twice daily). After 2 weeks, bronchoscopy showed significant shrinkage of the fungal mass. One month later, the anastomosis appeared normal with no microbiological evidence of fungal infection (Figure 1e and f). Plasma levels of PC945 ranged from 2 to 6.7 ng/ml in both subjects. PC945 was well tolerated with no adverse effects. PC945 is a non-irritant when inhaled; exhibits a combination of high potency, lung retention, and low oral bioavailability; and sustains effective anti-fungal concentrations in the lung with minimal systemic exposure.4Colley T Alanio A Kelly SL et al.In vitro and in vivo antifungal profile of a novel and long-acting inhaled azole, PC945, on Aspergillus fumigatus infection.Antimicrob Agents Chemother. 2017; 61 (e02280-16)Crossref Scopus (33) Google Scholar PC945 acts by inhibiting lanosterol 14α-demethylase, depleting ergosterol in fungal membranes. It produces synergistic effects in combination with other triazoles.5Colley T Sehra G Daly L et al.Antifungal synergy of a topical triazole, PC945, with a systemic triazole against respiratory Aspergillus fumigatus infection.Sci Rep. 2019; 9: 9482Crossref PubMed Scopus (16) Google Scholar Phase 3 studies are due to start in 2021 to assess PC945 to treat various forms of pulmonary aspergillus disease as part of a combined anti-fungal regimen. Our initial experience suggests a potential role for PC945 in the treatment of refractory Aspergillus bronchial anastomotic infection.