Van Matre et al. Ann Clin Microbiol Antimicrob (2019) 18:13 https://doi.org/10.1186/s12941-019-0311-3 Annals of Clinical Microbiology and Antimicrobials RESEARCH Open Access Comparative evaluation of isavuconazonium sulfate, voriconazole, and posaconazole for the management of invasive fungal infections in an academic medical center Edward T. Van Matre1 , Shelby L. Evans2, Scott W. Mueller3, Robert MacLaren3, Douglas N. Fish3 and Tyree H. Kiser3,4* Abstract Background: Invasive fungal infections are a major cause of morbidity and mortality. Newer antifungals may provide similar efcacy with improved safety compared to older more established treatments. This study aimed to compare clinically relevant safety and efcacy outcomes in real world patients treated with isavuconazole, voriconazole, or posaconazole. Methods: This single center retrospective matched cohort study evaluated adults between January 2015 and Decem- ber 2017. The primary outcome was a composite safety analysis of antifungal related QTc prolongation, elevated liver function tests (> 5 times ULN), or any documented adverse drug event. Key secondary outcomes included: individual safety events, 30-day readmissions, magnitude of drug interactions with immunosuppressive therapy, and overall cost. Results: A total of 100 patients were included: 34 patients in the voriconazole group and 33 patients within each of the isavuconazole and posaconazole groups. The composite safety outcome occurred in 40% of the total cohort and was diferent between isavuconazole (24.2%), voriconazole (55.9%), and posaconazole (39.4%; p 0.028). Change in QTc (p < 0.01) and magnitude of immunosuppression dose reduction (p 0.029) were diferent between= the three groups. No diferences in mortality, length of stay, readmission, or infection= recurrence were observed between groups (p > 0.05 for all). The overall medication cost, when including therapeutic drug monitoring, was not diferent between treatments (p 0.36). = Conclusions: Patients treated with isavuconazole resulted in fewer composite safety outcomes, driven by decreased incidence of QTc prolongation, compared to patients treated with voriconazole or posaconazole. Overall drug cost was not signifcantly diferent between the treatment therapy options. Keywords: Isavuconazole, Voriconazole, Posaconazole, Mycoses, Aspergillus Background data, invasive aspergillosis is the most common type of Invasive fungal infections are a major cause of morbid- fungal infection in stem cell transplant patients and the ity and mortality among patients, particularly those with second most common fungal infection in solid organ a compromised immune system. According to published transplant patients, with an incidence of 19% during a surveillance period from 2001 to 2006 [1, 2]. Te 1-year survival rate associated with invasive aspergillosis infec- *Correspondence: [email protected] 4 Department of Clinical Pharmacy, University of Colorado Anschutz tions is roughly 59% in solid organ transplant patients Medical Campus, 12850 East Montview Blvd, mailstop C238, Aurora, CO and 25% among stem cell transplant patients [1]. Mucor- 80045, USA mycosis was identifed as the third most common cause Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Van Matre et al. Ann Clin Microbiol Antimicrob (2019) 18:13 Page 2 of 7 of fungal infections in stem cell transplant patients and prisoners, pregnancy) as defned by institutional review while rarer than invasive aspergillosis infections, the all- board. cause mortality rate in these patients is estimated at 54% [3]. Primary end point Invasive mucormycosis and aspergillosis are difcult Te primary outcome evaluated was a composite safety infections to treat and the cost of therapy adds additional outcome (occurrence of any of the following safety events burden to the United States healthcare system. In 2009, it after the initiation of an antifungal): QTc prolongation was estimated that each case of mucormycosis results in (> 470 ms for females and > 450 ms for males), liver func- an average cost of $97,743, totaling over $50 million per tion tests fve times the upper limit of normal (ALT > 260 year [4]. Monitoring of therapeutic drug levels for certain units/L and AST > 195 units/L), or any documented medications further adds to this already high treatment antifungal treatment related adverse event based on pri- cost. Current frst-line treatment for invasive aspergillo- mary team documentation within the electronic medical sis, based on the Infectious Disease Society of America record. guidelines, is voriconazole. Te primary alternative ther- apy options are isavuconazole and liposomal or lipid for- Secondary end points mulations of amphotericin B. Posaconazole is a third-line Te secondary outcomes evaluated were the individual agent for patients with clinical failure or adverse events. components of the composite outcome, percent change Echinocandin therapy may be considered as combination in QTc length from baseline; percent change in calcineu- therapy with a triazole or as salvage therapy [5]. Current rin inhibitor serum concentration from baseline using frst-line treatment for invasive mucormycosis is ampho- the following equation: tericin B, in patients who can tolerate the nephrotoxic Baseline total daily dose − Adjusted total daily dose side efects. Other options include posaconazole and Baseline steady state serum concentration Adjusted steady state serum concentration × 100 Baseline total daily dose isavuconazonium sulfate (isavuconazole) for alternate or Baseline steady state serum concentration step-down therapy [6]. total cost of inpatient antifungal therapy per day, utilizing In recent clinical trials isavuconazole showed similar average wholesale price (AWP) and hospital cost for ther- efcacy and improved safety compared to voriconazole apeutic drug monitoring; all-cause in-hospital mortality; for the treatment of invasive molds and mucormycosis hospital length of stay; and intensive care unit length of [7, 8]. Te use of isavuconazole in a variety of clinical stay. settings is expanding. Tis study aimed to evaluate the utilization of isavuconazole at a single center academic Statistical analysis medical center, and to comparatively evaluate efective- In order to minimize selection bias and ensure simi- ness, safety, and cost between isavuconazole, voricona- lar comparator groups, patients were grouped based on zole, and posaconazole. indication for antifungal use, concomitant disease pro- cesses, and baseline demographics (e.g. age, neutropenia, Methods renal dysfunction, and hepatic dysfunction). Similar fre- Study design quency of each group were included. Based on previously reported adverse event rates of approximately 60% [7], Tis was a retrospective cohort study conducted at 30 patients were needed in each group to detect a 30% the University of Colorado Hospital between January diference in the primary outcome between groups with 2015 and December 2017. Te study was reviewed and 80% power and an alpha of 5%. approved by the Colorado Multiple Institutional Review Over the entire study period 35 patients received isa- Board. Patients were identifed through the University vuconazole, 53 patients received posaconazole, and 115 of Colorado Hospital’s electronic medical records using patients received voriconazole. Given the disparity of use medication usage reports. Study data were collected and between the groups over the study period patients were managed using REDCap electronic data capture tools matched to provide a balanced comparative evaluation. hosted at the University of Colorado Anschutz Medi- Patients were primarily matched on indication of use cal Campus [9]. Patients were included within the study (treatment vs prophylaxis), followed by admission diag- if they were 18 years of age and received isavucona- ≥ nosis and treatment month. Te isavuconazole treatment zonium sulfate (isavuconazole), voriconazole, or posa- group was used as the reference for patient matching. conazole for active treatment of confrmed or suspected Categorical data were compared utilizing Chi squared fungal infection as part of routine clinical care. Patients test, if statistical signifcance was found pairwise compar- were excluded if they were vulnerable subjects (e.g. isons were performed between the groups. Continuous Van Matre et al. Ann Clin Microbiol Antimicrob (2019) 18:13 Page 3 of 7 normally distributed data were compared utilizing and posaconazole groups respectively. Of the 100 analysis of variance test followed by pairwise t-test, and patients included within the study a majority were male non-normally distributed data were compared utilizing (54%) with a mean age of 55.9 years of age and a major- Kruskal–Wallis test followed by pairwise Mann–Whitney ity of patients (62%) were admitted to UCH with a pri- U tests. All tests were two sided with an α level of 5% and mary oncologic diagnosis.