Evaluation of targeted versus universal prophylaxis for the prevention of invasive fungal infections following lung transplantation

Abstract

Background Antifungal prophylaxis to prevent invasive fungal infections (IFI) is widely used following lung transplantation, but the optimal strategy remains unclear. We compared universal with targeted antifungal prophylaxis for effectiveness in preventing IFI. Methods Adult patients who underwent lung transplantation at the University of Michigan from /1 July 2014‐31 December 2017 were studied for 18 months post‐transplant. Universal prophylaxis consisted of itraconazole with or without inhaled liposomal amphotericin B. Using specific criteria, targeted prophylaxis was given with voriconazole for patients at risk for invasive pulmonary aspergillosis (IPA) and with fluconazole or micafungin for patients at risk for invasive candidiasis. Risk factors, occurrence of proven/probable IFI, and mortality were analyzed for the two prophylaxis cohorts. Results Of 105 lung transplant recipients, 84 (80%) received a double lung transplant, and 38 (36%) of patients underwent transplant for pulmonary fibrosis. Fifty‐nine (56%) patients received universal antifungal prophylaxis, and 46 (44%), targeted antifungal prophylaxis. Among 20 proven/probable IFI, there were 14 IPA, 4 invasive candidiasis, 1 cryptococcosis, and 1 deep sternal mold infection. Six (10%) IFI occurred in the universal prophylaxis cohort and 14 (30%) in the targeted prophylaxis cohort. Five of 6 (83%) IFI in the universal prophylaxis cohort, compared with 9/14 (64%) in the targeted prophylaxis cohort, were IPA Candida infections occurred only in the targeted prophylaxis cohort. The development of IFI was more likely in the targeted prophylaxis cohort than the universal prophylaxis cohort, HR = 4.32 (1.51‐12.38), P = .0064. Conclusions Universal antifungal prophylaxis appears to be more effective than targeted antifungal prophylaxis for prevention of IFI after lung transplant.

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

“…Non-comparative studies have shown a low incidence rate of IA < 5% with either n-AmBd or nebulized lipid formulations of AmB alone, or in association with systemic antifungal prophylaxis [ 18 , 53 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 ] ( Supplementary Tables S4 and S5 ). The use of n-AmBd resulted in a significant decrease in IA incidence in several prospective and retrospective studies, in comparison with historical controls without antifungal prophylaxis [ 4 , 117 , 118 , 119 , 120 ].…”

Antifungal Prophylaxis After Lung Transplantation: Where Are We Now?

“…Despite several studies evaluating the efficacy of triazole agents for antifungal prophylaxis after LTx, there are several limitations to currently available data: the majority of studies are single-center and retrospective, have a small sample size, are and noncomparative, and nearly all comparative studies used a nonrandomized, sequential des-ign. 11,13,16,18,19 These studies also assessed different prophylactic strategies and treatment durations, and different immunosuppressive regimens were used. Because of the scarce high-quality data, much of the evidence supporting antifungal prophylaxis after LTx is extrapolated from other immunosuppressed patient groups, such as other solid organs (liver and kidney) transplant recipients and bone marrow transplant recipients, in which the efficacy of antifungal prophylaxis is more clearly established.…”

“…Several studies describe the efficacy of universal prophylaxis in preventing post-transplant fungal infections. 2,5,11,12,[14][15][16] However, known clinical risk factors for fungal infection after LTx include single-lung LTx, ischemia of the bronchial anastomosis, anastomotic complications, mechanical interventions, hypogammaglobulinemia, cytomegalovirus infection or viremia, pre-or post-transplant fungal airway colonization, rejection and augmented immunosuppression, and a complicated postoperative course. 5,7,8,17,18 Based on these risk factors, one may decide to adopt a clinically targeted prophylaxis strategy (ie, before any post-transplant fungal pathogen or serologic marker of fungus is isolated) in those cases, which has also shown to be effective.…”

“…5,7,8,17,18 Based on these risk factors, one may decide to adopt a clinically targeted prophylaxis strategy (ie, before any post-transplant fungal pathogen or serologic marker of fungus is isolated) in those cases, which has also shown to be effective. [16][17][18][19] A major limiting factor for evidence-based clinical decisionmaking; however, is the lack of randomized controlled trials comparing universal prophylaxis versus targeted prophylaxis. A prior (2016) meta-analysis on antifungal prophylaxis in adult LTx recipients, involving universal and targeted antifungal prophylaxis strategies, showed a reduction in the rate of invasive aspergillosis with universal anti-Aspergillus prophylaxis.…”

Additivity interactions between fluconazole and citrus essential oils to<i> Aspergillus fumigatus</i>

“…Fluconazole is used in some experimental studies as a standard anti-fungal drug against, among others: Aspergillus niger, Aspergillus flavus, Alternaria alternata [38][39][40]. The minimum concentration of fluconazole that inhibited the growth of Aspergillus fumigatus in 50% was 16 μg/ml [41].…”