Nebulized Amphotericin B in Mechanically Ventilated COVID-19 Patients to Prevent Invasive Pulmonary Aspergillosis: A Retrospective Cohort Study

Abstract

IMPORTANCE: Despite high mortality rates of COVID-19-associated pulmonary aspergillosis (CAPA) in the ICU, antifungal prophylaxis remains a subject of debate. We initiated nebulized conventional amphotericin B (c-AmB) as antifungal prophylaxis in COVID-19 patients on invasive mechanical ventilation (IMV). OBJECTIVES: To assess the CAPA incidence in COVID-19 patients on IMV treated with and without nebulized c-AmB as antifungal prophylaxis. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of consecutive COVID-19 patients admitted to our adult 17-bed ICU in a university-affiliated general hospital in Ede, The Netherlands, between January 25, 2021, and July 9, 2021. Patients not requiring IMV or transferred from or to another ICU were excluded. From April 9, 2021, daily nebulized amphotericin B in all patients on IMV was initiated. MAIN OUTCOMES AND MEASURES: Bronchoscopy with bronchoalveolar lavage (BAL) was performed in case of positive cultures for Aspergillus from the respiratory tract and/or unexplained respiratory deterioration. Incidence of probable and proven CAPA was compared between patients treated with and without nebulized antifungal prophylaxis using Pearson chi-square test. RESULTS: A total of 39 intubated COVID-19 patients could be analyzed, of which 16 were treated with antifungal prophylaxis and 23 were not. Twenty-six patients underwent bronchoscopy with BAL. In patients treated with antifungal prophylaxis, the incidence of probable/proven CAPA was significantly lower when compared with no antifungal prophylaxis (27% vs 67%; p = 0.047). Incidence of tracheobronchial lesions and positive Aspergillus cultures and BAL-galactomannan was significantly lower in patients treated with antifungal prophylaxis (9% vs 47%; p = 0.040, 9% vs 53%; p = 0.044, and 20% vs 60%; p = 0.047, respectively). No treatment-related adverse events and no case of proven CAPA were encountered in patients receiving antifungal prophylaxis. CONCLUSIONS AND RELEVANCE: Nebulization of c-AmB in critically ill COVID-19 patients on IMV is safe and may be considered as antifungal prophylaxis to prevent CAPA. However, a randomized controlled trial to confirm this is warranted.

High Burden of COVID-19-Associated Pulmonary Aspergillosis in Severely Immunocompromised Patients Requiring Mechanical Ventilation

“…Moreover, we showed that this association persists in the vaccination era. To date, only small observational studies have described the effect of antifungal prophylaxis in patients with severe COVID-19 [ 31–34 ]. Each of these studies showed a benefit of inhaled or systemic prophylaxis on the incidence of CAPA.…”

The battle against fungi: lessons in antifungal stewardship from COVID 19 times

“…Posaconazole, administered through a gastric tube or intravenously, and inhaled AmB have been investigated. Prophylaxis significantly reduced the incidence of CAPA in three of these investigations [54] , [55] , [56] , but did not influence survival in the two studies [54 , 55] that reported survival data. There are currently insufficient data to recommend prophylaxis.…”

“…Several studies have investigated alternative management strategies, including the use of nebulized or systemic antifungal prophylaxis and diagnostic driven strategies, but firm conclusions cannot be drawn at this stage [41 , 53] . Only six studies to date have looked into antifungal prophylaxis for CAPA [54] , [55] , [56] , [57] , [58] , [59] . Posaconazole, administered through a gastric tube or intravenously, and inhaled AmB have been investigated.…”

Diagnosis and Antifungal Prophylaxis for COVID-19 Associated Pulmonary Aspergillosis

“…Reported adverse effects of the prophylaxis included bronchospasm in 8.8% of patients and drug buildup in the expiratory limb’s filter of the ventilator. A retrospective cohort study out of the Netherlands started daily conventional nebulized amphotericin B as antifungal prophylaxis for COVID-19 patients on invasive mechanical ventilation [ 72 ]. The study used 10 mg twice daily for 22 days followed by 5 mg four times daily for an unspecified total duration.…”

“…However, nebulized drug deposition in ventilated lungs does not have as much supportive data as nebulized prophylaxis in non-ventilated patients. Additionally, nebulized prophylaxis may lead to the clogging of ventilator filters, though this has not been felt to be clinically significant [ 72 ]. If we were to select antifungal prophylaxis for our patients, we would elect to pursue inhaled amphotericin B, as this medication is slightly better supported than posaconazole for CAPA prophylaxis specifically.…”