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AbstractBackgroundCurrent guidelines recommend immunomodulators, tocilizumab or baricitinib, for the management of severe coronavirus disease‐2019 (COVID‐19) in patients with increasing oxygen requirements. Given their immunosuppressive effects, there is a concern for higher rates of infection among transplant recipients.MethodsA retrospective cohort study of transplant patients with severe COVID‐19 between April 2020 and January 2022 was performed at the Mayo Clinic. The primary outcome was incidence of secondary infections after COVID‐19 diagnosis. Secondary outcomes were 90‐day mortality, ventilatory days, and thromboembolic events.ResultsA total of 191 hospitalized transplant patients were studied, including 77 (40.3%) patients who received an immunomodulator. Overall, 89% were solid organ transplant recipients, with kidney as the most common transplanted organ (50.3%). The majority (89.0%) required oxygen supplementation on admission, and 39.8% of these patients required mechanical ventilation during the hospital course. There was no significant difference in the incidence of secondary infections between those who received or did not receive an immunomodulator (p = .984). Likewise, there was no difference in 90‐day mortality between patients who received or did not receive an immunomodulator (p = .134). However, higher mortality was observed among patients that developed a secondary infection (p < .001).ConclusionThe use of immunomodulators in transplant patients with severe COVID‐19 was not significantly associated with an increased risk of secondary infections. Secondary infections were associated with higher risk of all‐cause mortality. Future studies of larger cohorts are needed to explore the effect of immunomodulators on survival among transplant patients with COVID‐19. image

AbstractBackgroundItraconazole is the recommended first‐line treatment for mild‐to‐moderate blastomycosis and consolidation treatment of moderate‐to‐severe disease. Itraconazole is metabolised into three metabolites, including an active metabolite hydroxy‐itraconazole. Literature provides little evidence indicating whether therapeutic drug monitoring targets should be based on itraconazole parent compound alone or a sum of itraconazole and hydroxy‐itraconazole serum concentrations.ObjectivesThis study aims to compare clinical outcomes and adverse drug events (ADEs) of combined itraconazole and hydroxy‐itraconazole concentrations versus itraconazole parent compound alone in patients with blastomycosis.Patients/MethodsThis study was a retrospective cohort review of patients ≥18 years with probable or proven Blastomyces infection who received itraconazole with at least one documented serum itraconazole concentration. The primary outcome was rate of partial or complete treatment response across three patient groups: (1) Itraconazole parent compound >1.0 mcg/ml (parent), (2) parent compound <1.0 mcg/ml, but a combined itraconazole and hydroxy‐itraconazole >1.0 mcg/ml (combined) and (3) failure to achieve a combined or parent concentration >1.0 mcg/ml (subtherapeutic) for >75% of the duration of itraconazole therapy.ResultsA total of 80 patients were included (parent = 32, combined = 36, subtherapeutic = 12). No statistically significant difference was observed for rate of partial or complete treatment response (97% parent vs 94% combined, p = .99). Significantly higher mortality due to blastomycosis was observed in patients in the subtherapeutic group (0% parent vs 3% combined vs 25% subtherapeutic, p = .01).ConclusionsThis study supports an itraconazole therapeutic target combining itraconazole and hydroxy‐itraconazole >1.0 mcg/ml for blastomycosis treatment.

Abstract Background Isavuconazole (ISA) is a relatively recent triazole antifungal with several attractive qualities and so increased clinical experience and data on the use of ISA are desirable. However, the data on the pattern of ISA use in invasive fungal infections (IFI) is limited. Methods We conducted a retrospective study of patients with probable or proven IFI treated with ISA at Mayo Clinic from 1/1/2015 to 4/1/2020 to examine temporal trends and characteristics of ISA use. Results The use of ISA rose over this period, from 4 cases in 2015 to 42 cases in 2019. Of 131 patients identified, ISA was used as the initial antifungal in 15 (11.5%) patients and as the secondary agent in 116 (88.5%) patients. The most cited reasons for choosing ISA as first-line therapy were drug-drug interactions (5, 33%) and baseline QTc prolongation (3, 20%). In cases of ISA used as a secondary agent, the reasons for transitioning to ISA were QTc prolongation (22, 19%), followed by judged failure of the primary therapy (20, 17%), drug-drug interactions (12, 10%), and various toxicities with the first agent. ISA was discontinued early in 81 (62%) patients. Common reasons for early discontinuation were patient death or comfort care (27, 33%), intolerance (18, 22%), failure of therapy (17, 21%), cost or access (6, 7%), drug-drug interaction (3, 4%), issues with absorption or drug delivery (3, 4%), and microbe susceptibility (1, 1%). ISA was judged successful and used as definitive treatment in the remaining 50 (38%) patients. About 30 patients took &gt;1 year of ISA, and no major adverse effects from long-term therapy were noted. Conclusion Although ISA is approved for pulmonary aspergillosis and mucormycosis, we found that few patients were treated with ISA as either primary or salvage therapy. In cases where it was used, shortening the QTc and fewer drug-drug interactions were its most attractive qualities. Although it is a newer azole, the morbidity common with other antifungals should prompt more studies on ISA’s efficacy to increase clinicians’ confidence in this option. Disclosures All Authors: No reported disclosures.

Abstract Background The role of sequential blood culture time to positivity (TTP) as a surrogate marker for bacterial load and as a prognostic indicator in S. aureus bacteremia (SAB) is not well established in the literature. Methods We performed a single healthcare system, multi-site, retrospective review of adult patients with positive blood culture for S. aureus between January 2019 and December 2019. Sequential TTP was defined as the TTP of the first subsequent blood cultures obtained from patients with SAB for at least 24 hours. We adapted the previously described TTP ratio of &lt; 1.5 as the cut-off for study groups. Infective endocarditis (IE) was defined according to modified Duke’s criteria. High-grade bacteremia was defined as the growth of the organism in two or more sets of blood cultures or growth in &gt;50% of all bottles collected. Descriptive, comparative statistics and survival analysis were performed using Python 3 and IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp. Results A total of 602 patients with SAB were identified, and 186 patients who met the study criteria were included. Sixty-nine patients (37%) were female, and the mean age was 63.6 years. Patients with initial TTP &lt; 12 hours had higher 30-day and 90-day mortality than those with initial TTP ≥ 12 hours. Patients with TTP ratio of &gt; 1.5 had higher rates of cardiac prosthetic device (30 [26.1%] vs. 9 [12.7%], p = .03) and high-grade bacteremia (106 [92.2%] vs. 56 [78.9%], p = .01). In univariate analysis, history of myocardial infarction, cardiac prosthetic device, and findings of high-grade bacteremia and native valve vegetation in echocardiogram were significant predictors for a TTP ratio of &lt; 1.5. In multivariate analysis, native valve vegetation (OR 2.4; 95% CI 1.2-4.84), and high-grade bacteremia (OR, 0.3; 95% CI, 0.13- 0.77) were independent predictors (Table 1 and 2). No differences in 30- day or 90-day survival based on the TTP ratio were seen (Figure 1). Figure 1.Kaplan-Meier (KM) curves and log rank test results based on time to positivity (TTP) of initial blood cultures and TTP ratio of sequential to initial blood culture The X-axis represents the days elapsed from the initial blood culture collection. Number of patients at risk and events are given below the x-axis for each group. 30-day and 90-day survival rates were significantly lower in patients with initial TTP of &lt; 12 hours compared with those with ≥ 12 hours. There were no statistically significant differences in survival based on TTP ratio. Conclusion In patients with SAB, a second TTP to first TPP ratio of &gt; 1.5 was associated with higher rates of presence of the cardiac prosthetic device and high-grade bacteremia. Initial TTP &lt; 12 hours was associated with lower survival; however sequential TTP ratio didn’t predict mortality. Disclosures All Authors: No reported disclosures.

Abstract Background Diagnosing acute Q fever is challenging partly due to the non-specific and self-limited course of illness in the majority of cases. It is important to identify and treat patients who are at increased risk for progression to persistent disease to prevent future complications. We describe the demographics, clinical presentation, and treatment of patients diagnosed with acute Q fever at our institution. Methods We identified all patients diagnosed with acute Q fever between December 2019 and March 2022. Patients 18 years or older who had a Q fever anti-phase II IgM ≥ 1:50 and anti-phase II IgG ≥ 200 were included. Patient with an anti-phase II IgG &lt; 200 were included if they had a fourfold rise in titers at follow-up within 3-6 weeks. Results Overall, 13 cases of acute Q fever were identified. Ages ranged between 32 and 68 years and 85% were men. The majority resided in the Midwest. A non-specific febrile illness was the most common presentation (11/13) (Table 1). Duration of symptoms predominantly ranged between 10 to 20 days. Elevated liver enzymes were noted in 7/13. Three had detectable Coxiella DNA in the blood during the acute phase using cell free DNA next generation sequencing but not using Coxiella PCR. Eleven patients had an exposure history. Overall, 6 patients received doxycycline monotherapy for a median of 14 days, while 7, who had risk factors for progression to chronic disease, received doxycycline and hydroxychloroquine for a median of 15 months. Among patients who followed-up, only one was restarted on therapy due to recurrence of symptoms. None of the patients developed infective endocarditis. Conclusion Acute Q fever is more frequently recognized, partly, because of increased awareness among physicians, however also possibly due to the increasing prevalence of the infection. In a cohort of 49 patients with Q fever at our institution between 2012 and 2018, 20 had acute Q fever, compared to 13 patients in this cohort. The infection predominantly affects men and the majority have an identifiable exposure history. Elevated CRP, abnormal liver enzymes, and detectable antiphospholipid antibodies were prevalent in our cohort. Patient with risk factors for progression into chronic disease were often placed on a longer course of a combination therapy in attempt to prevent chronic focal infections. Disclosures All Authors: No reported disclosures.

Abstract Background Posaconazole therapeutic drug monitoring (TDM) is widely utilized to assess therapeutic efficacy and safety (i.e., hepatotoxicity, QTc prolongation); however, little is known about clinical effects of very high serum posaconazole serum levels (i.e., ≥ 5000 mg/mL). Reported incidence rate of adverse drug reactions (ADRs) with posaconazole per most recent clinical trial was ∼30%. The primary objective was to compare the ADR incidence in patients with serum posaconazole levels of 3000-4999 ng/mL to ≥5000 ng/mL. Methods This retrospective cohort study included adult patients with a posaconazole serum level ≥3000 ng/mL from 1/1/2019 to 04/30/2021. The primary outcome was symptomatic ADR at time of first serum level ≥3000 ng/mL. Secondary outcomes were laboratory defined hepatoxicity, electrolyte and adrenal laboratory abnormalities, QTc changes, and dose changes in response to TDM. Patient outcomes were censored after the first serum level and were compared between groups using Fisher’s exact tests. Results Ninety patients met inclusion criteria, 80 with a level of 3000-4999 ng/mL and 10 with a level of ≥ 5000 ng/mL occurring at a median of 91 days (26-443) and 27 days (12-45) from posaconazole initiation, respectively. Majority of patients were immunocompromised (55.6% transplant recipients, 28.9% active malignancy, 5.6% other) with a split of treatment (50%) and prophylaxis (42.2%) indication. Symptomatic ADRs were very common in patients with posaconazole levels of ≥5000 ng/mL and 3000-4999 ng/mL (80% vs. 58.8%; p=0.31), primarily neurologic (49.1% overall) followed by gastrointestinal (32.7% overall). Hepatotoxicity was also common (≥5000 ng/mL 40% vs 3000-4999 ng/mL 23.4%, p=0.26). Fifty percent of patients had the posaconazole dose continued without change. Electrolytes and QTc results were similar between groups, but median overall QTc was borderline high (456 [IQR 435, 479]). Conclusion There are safety concerns for patients with serum posaconazole levels ≥3000 ng/mL. Posaconazole levels should be monitored and, importantly, dose adjusted according to serum level and patient symptoms for both treatment and prophylaxis indications. Disclosures Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.

Abstract Background Immunomodulators have been shown to improve the outcomes of patients with severe COVID-19. However, it is not known if tocilizumab or baricitinib use would be beneficial in transplant patients who are already receiving immunomodulating agents. Moreover, augmented immunomodulation may increase risk of opportunistic infection. There are few studies analyzing the outcomes and complications of these medications in this population. Methods This is a detailed review of the medical records of all transplant patients who received tocilizumab or baricitinib for COVID-19 indication at our multi-state transplant center from April 2020 to March 2022. Results A total of 57 transplant patients received tocilizumab (n=48) or baricitinib (n=9) for management of COVID-19. Baseline characteristics are in Table 1. 60% had received at least one dose of COVID-19 vaccine. At diagnosis, all patients were lymphopenic (median 0.4 x109 cells/L) with high CRP (median 76.8mg/L) and elevated IL-6 levels (median 145.5pg/ml.). The majority had reduction in transplant immunosuppression (75%) and received remdesivir (86%) and dexamethasone (90%). Majority were admitted to the ICU (68%), including 40% who required invasive mechanical ventilation (Table 2). Almost a third developed bacterial or fungal superinfection. Bacterial infections include respiratory cultures with Klebsiella spp, MRSA, P. aeruginosa, Enterobacter spp and Stenotrophomonas. Blood cultures were positive for Klebsiella spp, MDR P. aeruginosa, E faecalis. Fungal infections include three patients with Aspergillus spp infections who received antifungals. No statistical difference was seen in mortality between patients with infections and not infections group. No statistical difference was seen between type of transplants for infection or mortality. Mortality at 90 days was 46%. Conclusion Transplant patients who received tocilizumab or baricitinib for severe or critical COVID-19 have poor outcome. This case series found high rates of mortality and opportunistic superinfections after tocilizumab and baricitinib use compared to the current literature. Future directions include a matched case-control study to compare the outcomes in this population. Disclosures Raymund R. Razonable, MD, Gilead: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Novartis: DSMB|Regeneron: Grant/Research Support|Roche: Grant/Research Support.

Abstract Background Itraconazole is first-line treatment for mild-moderate blastomycosis and consolidation of moderate-severe disease. Itraconazole is metabolized to 3 metabolites, including an active metabolite hydroxy-itraconazole. The sum of itraconazole and hydroxy-itraconazole levels &gt; 1.0 mcg/mL is guideline recommended for treatment of invasive fungal infections; conversely, some experts suggest targeting a parent compound level alone &gt; 1.0 mcg/mL. This study aims to compare clinical outcomes and adverse drug reactions (ADRs) of combined itraconazole and hydroxy-itraconazole levels &gt; 1.0 mcg/mL versus itraconazole parent compound alone &gt; 1.0 mcg/mL in patients with blastomycosis. Methods This study is a single-center, retrospective chart review of patients ≥ 18 years with probable or proven Blastomyces infection who received itraconazole with at least one documented serum itraconazole level. The primary outcome was rate of partial or complete treatment response in patients with a combined itraconazole and hydroxy-itraconazole level &gt; 1.0 mcg/mL versus itraconazole parent compound &gt; 1.0 mcg/mL for &gt; 75% of measured levels. ADRs attributable to itraconazole were compared between the groups. Treatment response rates and ADRs were compared between groups using two proportion z-tests. Results Total of 80 patients were included: 36 = combined itraconazole and hydroxy-itraconazole &gt; 1.0, 32 = itraconazole parent alone &gt; 1.0, 12 = 75% of all levels &lt; 1.0. No statistically significant difference was observed between groups for blastomycosis rate of partial or complete treatment response (94.3% combined vs 96.6% parent, p=0.99). Significantly higher mortality was observed in patients failing to achieve itraconazole or itraconazole/hydroxy-itraconazole &gt; 1.0 (2.8% combined vs 0% parent vs 25% neither, p=0.01). There was no significant difference in total ADRs between the three groups (p=0.56). Conclusion This limited evidence supports an itraconazole therapeutic target combining itraconazole and hydroxy-itraconazole &gt; 1.0 for blastomycosis treatment. Disclosures Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.

Abstract Background Beta-lactam therapeutic drug monitoring (BL TDM; drug level testing) can facilitate improved outcomes in critically ill patients. Yet less than 20% of hospitals have implemented BL TDM. The purpose of this study was to characterize provider perceptions and key considerations for successful implementation of BL TDM. Methods This was a sequential mixed methods study from 2020 to 2021 of stakeholders at three academic medical centers with varying degrees of BL TDM implementation - Mayo Clinic (BL TDM not implemented), University of Florida Health Shands (partially implemented), and Royal Brisbane and Women’s Hospital (fully implemented). Stakeholders completed a survey to characterize their knowledge, perceptions, and experience with BL TDM. A diverse group of 30 respondents were then purposively sampled for semi-structured interviews. Results from the two strands were integrated, themes were identified, and findings were situated within implementation science frameworks. Results Among the 138 survey respondents (22% response rate), the majority were physicians (38%) and pharmacists (33%). 71% practiced in critical care and 21% in infectious diseases. The majority of respondents felt BL TDM was relevant to their practice and improved medication effectiveness and safety (Figure 1). Two implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation which was positively influenced by repeated exposure to evidence and expertise. The process of internalization seemed more complex with BL TDM than with other antibiotics (i.e., vancomycin). Organizational considerations relevant to BL TDM implementation included adequate physical and informational infrastructure, access to trained personnel, supportive governance/leadership, and robust process and workflow development. Conclusion We found broad enthusiasm about the relevance and potential benefits of BL TDM among stakeholders. Prior literature suggested the primary barrier to implementation was assay availability, but we identified many more individual and organizational attributes which impacted the scale and spread of BL TDM. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Allecra: Grant/Research Support|Merck: Advisor/Consultant|Nevakar: Advisor/Consultant|Nevakar: Grant/Research Support|Premier Healthcare Solutions: Honoraria|Spero: Advisor/Consultant|SuperTrans Medical: Advisor/Consultant|SuperTrans Medical: Grant/Research Support|Takeda: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant.