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Background: Invasive fungal infections (IFIs) are common following lung transplantation. Isavuconazole is unstudied as prophylaxis in organ transplant recipients. We compared effectiveness and tolerability of isavuconazole and voriconazole prophylaxis in lung transplant recipients., Methods: A single-center, retrospective study of patients who received isavuconazole (September 2015-February 2018) or voriconazole (September 2013-September 2015) for antifungal prophylaxis. IFIs were defined by EORTC/MSG criteria., Results: Patients received isavuconazole (n = 144) or voriconazole (n = 156) for median 3.4 and 3.1 months, respectively. Adjunctive inhaled amphotericin B (iAmB) was administered to 100% and 41% of patients in the respective groups. At 1 year, 8% of patients receiving isavuconazole or voriconazole developed IFIs. For both groups, 70% and 30% of IFIs were caused by molds and yeasts, respectively, and breakthrough IFI (bIFI) rate was 3%. Outcomes did not significantly differ for patients receiving or not receiving iAmB. Independent risk factors for bIFI and breakthrough invasive mold infection (bIMI) were mold-positive respiratory culture and red blood cell transfusion >7 units at transplant. Bronchial necrosis >2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI. Isavuconazole and voriconazole were discontinued prematurely due to adverse events in 11% and 36% of patients, respectively (P = .0001). Most common causes of voriconazole and isavuconazole discontinuation were hepatotoxicity and lack of oral intake, respectively. Patients receiving ≥90 days prophylaxis had fewer IFIs at 1 year (3% vs 9%, P = .02). IFIs were associated with increased mortality (P = .0001) and longer hospitalizations (P = .0005)., Conclusions: Isavuconazole was effective and well tolerated as antifungal prophylaxis following lung transplantation., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Isavuconazole (ISA) is a triazole antifungal with activity against yeasts and molds. We established a population pharmacokinetic (pop PK) model of intravenous (i.v.) ISA to identify covariates that affect pharmacokinetics, using plasma samples from solid-organ transplant (SOT) recipients receiving peritransplant prophylaxis. Samples ( n  = 471) from 79 SOT recipients were utilized for pop PK analysis using nonlinear mixed-effect modeling NONMEM software. ISA (i.v.) PK parameters were best described by a two-compartment model. Significant covariates were sex on clearance (∼53% higher in women than men) and body mass index on peripheral volume of distribution. Incorporating drug exposure into Monte Carlo simulations, we demonstrated that standard ISA dosing is likely to attain the PK-pharmacodynamic (PD) target (area under the concentration curve/MIC ratio [AUC/MIC]) for treatment effectiveness against almost all infections caused by Aspergillus fumigatus isolates exhibiting MICs of ≤0.5 μg/ml (modal MIC). In contrast, standard dosing is predicted to attain PK-PD targets against <20% of infections caused by Candida albicans and Candida glabrata isolates exhibiting MICs of ≥0.016 and ≥0.5 μg/ml, respectively (modal MICs). These data are consistent with our SOT program's experience with ISA breakthrough infections, where 3 of 4 were caused by C. glabrata for which probabilities of PK-PD target attainment (PTA) were only 70% and 0% for isolates with MICs of 0.25 μg/ml and 1 μg/ml. Our findings provide important new insights into how ISA use might be optimized following SOT., (Copyright © 2020 American Society for Microbiology.)

Isavuconazole may be useful in treating and preventing fungal infections in solid-organ transplant (SOT) recipients due to its safety profile and activity against Aspergillus and some Mucorales Isavuconazole has favorable pharmacokinetics based on clinical trials in various patient populations, but data are limited in SOT recipients. We evaluated the steady-state pharmacokinetics of isavuconazole in 26 SOT recipients receiving the drug intravenously for prophylaxis. There was moderate interpatient variability in isavuconazole pharmacokinetic parameters (coefficients of variation of 51% for the area under the plasma concentration-versus-time curve [AUC] and 59% for the trough plasma concentration [ C trough ]). AUC and steady-state C trough were significantly lower in women, patients with a body mass index of ≥18.5 kg/m 2 , and those receiving hemodialysis. Trough plasma concentrations were highly correlated with AUCs ( R 2 = 0.94) and can serve as a suitable measure of isavuconazole exposure in patients. In conclusion, moderate interpatient variability in isavuconazole exposure, the identification of factors associated with lower exposure, the recognition that C trough is a surrogate marker for AUC, and the availability of a simple analytical method suggest that therapeutic drug monitoring (TDM) may be useful for guiding treatment in at least some SOT recipients. Future studies are needed to correlate isavuconazole exposure with patients' clinical outcomes and to determine the clinical role of TDM., (Copyright © 2018 American Society for Microbiology.)

Background IFI is a significant complication following lung transplant (LT). VOR was universal antifungal px in our LT program from 2004 to October 2015, at which time px was changed to ISA. We compared the efficacy and tolerability of VOR vs. ISA px in LTR. Methods We reviewed all LTR from September 2013 to February 2018 who received VOR or ISA Px. The standard duration of px was 3 or 4 months following basiliximab and alemtuzumab induction, respectively. All patients were followed for ≥1 years post-Tx. IFI was defined by revised EORTC/MSG criteria. Results In total, 310 LTR were included, 149 and 161 of whom received ISA and VOR px, respectively. There was no difference in demographics, underlying diseases, single vs. double LT, or induction therapy (alemtuzumab vs. basiliximab) between the 2 groups. At 1-year after LT, 9% (14) and 8% (13) of patients in ISA and VOR groups developed IFI, respectively (P = 0.5). 5% (7) and 3% (5) of patients developed breakthrough (BT) IFI during ISA and VOR px, respectively (P = 0.6; Figure 1, P = 0.4, Kaplan-–Meier). ISA BT included pneumonia (PNA, 2), endobronchial IFI (2), mediastinitis (1), chest wall IFI (1), and candidemia (1). ISA BT patients were infected with Aspergillus fumigatus (3; 2 with ISA MIC = 0.5 µg/mL, 1 MIC = 1 µg/mL), black mould (1), and yeasts (3; 2 C. glabrata , 1 C. albicans). VOR BT IFI included PNA (2), endobronchial IFI (1), empyema (1), and chest wall IFI (1). VOR BT IFIs were due to A. ustus , A. niger , A. lentulus , black mould, and Rhizopus spp (1 each). All Aspergillus VOR BT isolates exhibited VOR MIC ≥2 µg/mL. Patients with IFI were more likely to have positive pre-LT respiratory fungal culture (P = 0.01) and grade ≥3 ischemic reperfusion injury (IRI) post-LT (P = 0.01). VOR and ISA were prematurely discontinued in 53% (85) and 14% (21) of patients due to adverse events, respectively (P < 0.0001). Hepatotoxicity was more common with VOR (22%, 35) than ISA (5%, 7) (P < 0.0001). IFI was an independent risk factor for death at 1 year (Figure 2, P < 0.0001, Kaplan–Meier). Conclusion ISA was as effective as VOR in preventing IFI in LTR, and significantly better tolerated. Pre-LT fungal culture positivity and grade ≥3 IRI post-LT were risk factors for the development of IFI. IFI within 1-year post-LT had a significant impact on mortality Disclosures Fernanda P. Silveira, MD, MS, FIDSA, Ansun: Grant/Research Support; Qiagen: Grant/Research Support; Shire: Grant/Research Support; Whiscon: Grant/Research Support. [ABSTRACT FROM AUTHOR]

Background Despite increasing recognition of aspergillosis complicating severe influenza and its associated high fatality in Europe, incidence and features of the disease in the United States are unknown. Methods We reviewed all influenza cases requiring ICU admission from 2009 to 2019 at our center. Results 262 patients with influenza required ICU admission. 4% (10) developed IFI at median 2d after influenza diagnosis. 80% (8/10) of patients with IFI were infected with influenza A vs. 88% (221/252) without IFI. 20% were on steroids at the time of IFI diagnosis. 70% of IFI required mechanical ventilation. Types of IFI were pneumonia (70%, 6 Aspergillus and 1 Wangiella), endobronchial IFI (20%, 1 each with Aspergillus and Lictheimia), and Coccidioides fungemia (10%). 4% (10) of patients were fungal colonized, but did not have IFI (5 A. fumigatus , 1 A. terreus , 4 Penicillium). CT findings of IFI included nodules (4), cavitation (3), and ground-glass opacities (2). Serum galactomannan (GM) was positive in 3 (43%). Median time to antifungal therapy (AF) was 2 days. Triazoles were prescribed to all 7 patients with aspergillosis. Posaconazole and amphotericin B were AF for patients with Wangiellaand Lichteimia, respectively. Patients with C. immitis fungemia died before AF. Median duration of AF was 60 days among survivors. Patients with IFI required acute hemodialysis more frequently than colonized patients (60% vs. 0%, P = 0.01). 30-day mortality was 60% (6/10) and 20% 92/10) in patients with IFI and colonization, respectively (P = 0.2). Patients with IFI had significantly higher in-hospital and 60-day mortality than those without IFI (Fig 1, P = 0.009). Conclusion Our rate of post-influenza IFI (4%) was lower than reported in Europe (~15%), which might stem from a lack of systematic BAL GM testing at our center, over-reliance on GM to make diagnoses in Europe, and/or differences in pt populations and clinical practices in treating severe influenza. IFI and fungal colonization rates were similar at our center, highlighting the importance of using well-defined criteria to define disease. Given the high mortality of post-influenza IFI, priority should be given to defining risk factors that might identify patients for targeted AF prophylaxis. In using AF, it is important to recognize that Aspergillus is not the only cause of IFI. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]