Enzler, Mark J.

Background: Itraconazole is the preferred antifungal agent for mild to moderate histoplasmosis and step-down therapy following amphotericin B treatment. Although hydroxy-itraconazole, a major metabolite of itraconazole, displays antifungal activity comparable with that of the parent compound, its role in therapeutic drug monitoring targets for histoplasmosis remains uncertain. Methods: The objective was to compare clinical outcomes and adverse events using itraconazole parent-compound concentrations alone versus combined itraconazole and hydroxy-itraconazole concentrations in patients treated for histoplasmosis. This retrospective cohort study included adults with probable or proven histoplasmosis who received itraconazole and had at least 1 documented serum concentration. The primary outcome was clinical response across 3 groups: (1) parent (itraconazole parent-compound concentration >1.0 mcg/mL), (2) combined (parent-compound concentration <1.0 mcg/mL with combined itraconazole plus hydroxy-itraconazole >1.0 mcg/mL), and (3) subtherapeutic (failure to reach either threshold). Treatment response and adverse events were analyzed using the Fisher exact test. Results: Among 108 patients (parent, n = 40; combined, n = 40; subtherapeutic, n = 28), response rates differed across groups (parent (95%); combined (90%); subtherapeutic (67.9%); P = 0.006). There was no difference between the parent and combined groups. Adverse events did not differ, although drug discontinuation occurred more frequently in the subtherapeutic group (parent (5%); combined (20%); subtherapeutic (25%); P = 0.04). Conclusions: Patients who failed to achieve either an itraconazole concentration >1 mcg/mL or a combined itraconazole plus hydroxy-itraconazole concentration >1 mcg/mL had lower response rates. Similar outcomes among patients achieving the itraconazole target alone and those achieving the combined target suggest that hydroxy-itraconazole concentrations may contribute to therapeutic drug monitoring targets in histoplasmosis.

Itraconazole is the recommended first-line antifungal agent in blastomycosis treatment. However, pharmacokinetic limitations and adverse drug events may necessitate the use of alternative antifungal agents. The primary objective of the study was to retrospectively describe a cohort of patients with blastomycosis who received voriconazole (as partial or complete therapy), for complete or partial treatment, compared to those who received itraconazole alone. Secondary objectives included rationale for voriconazole selection, treatment response, mortality, and adverse drug events. This retrospective multicenter cohort study included adult patients with proven/probable blastomycosis who received itraconazole or voriconazole. Treatment response was evaluated at one year or end of therapy, whichever came first. Mortality outcomes were assessed within 7 days of the last documented azole dose. Propensity score weighting and subgroup analysis were utilized to control confounding variables between cohorts. A total of 119 patients receiving itraconazole and 25 receiving voriconazole as complete or partial treatment were included. Voriconazole was often selected for CNS involvement or after intolerance to alternative azoles. After propensity score weighting, no significant difference in complete or partial treatment response was observed. Rates of all-cause mortality and blastomycosis-related mortality were numerically higher in the voriconazole cohort. Adverse drug event rates were similar between cohorts; however, discontinuation due to adverse events was more common in the voriconazole cohort. Voriconazole was most utilized for the treatment of blastomycosis in cases with CNS involvement or intolerance to other azoles. A statistically significant difference in response rate was not identified between voriconazole-containing or itraconazole-treated patients; however, given limited sample sizes, further data is needed to assess the equivalency of these agents in the treatment of blastomycosis.

Abstract Patent foramen ovale (PFO) has a prevalence of approximately 25%. Its association with pyogenic brain abscess (PBA) is unclear. We reviewed adults with PBA and known PFO status from 1 January 2009 through 31 December 2021 at Mayo Clinic. High PFO prevalence (40.5%) was seen. PBA patients with PFO had distinct abscess characteristics but unchanged 1-year, all-cause mortality.

Abstract Background Leishmaniasis is a rare protozoan parasitic disease transmitted through the bite of infected Phlebotomus and Lutzomyia sandflies. Clinical presentation is variable due to numerous species and host immunity differences. We present our clinical experiences with CL to guide timely diagnosis and treatment in returning travelers. Methods We retrospectively analyzed a cohort of adult patients 18+ years old who were diagnosed with CL from 2005 and 2025. We describe the demographic, clinical, and diagnostic features of CL. Results Biopsy-confirmed CL was diagnosed in 20 returning travelers (Table 1) from various endemic regions, most commonly Costa Rica (Fig. 1). The median time from travel to symptom onset was 36.5 days (SD 102), with an additional 75.5 days (SD 87) prior to biopsy diagnosis. All patients were evaluated by dermatology and 70% were evaluated by infectious disease (n=14). On initial presentation, lesions were described as ulcerated (50%, n=10), nodular (30%, n=6), painful (20%, n=4), and necrotic (10%, n=2; Fig. 2). Most lesions were located on the upper extremity (55%, n=11), followed by the face (35%, n=7), lower extremity (30%, n=6), and trunk (15%, n=3). 15% of individuals (n=3) had constitutional symptoms. No patients had definitive mucosal involvement, however, 10% (n=2) endorsed lip edema. No patients had visceral involvement. Species level identification occurred in 14 cases (70%), of which the most common was L.V. panamensis (50%), L.L. mexicana (21%), L. V. guyanensis (14%), L. L. tropica (7%), and L. V. braziliensis (7%). Initial treatments included azoles, liposomal amphotericin B (AmBisome), and miltefosine (each 20%); cryotherapy and parenteral pentamidine (each 10%); with compounded topical paromomycin added in 15% of cases. 35% of individuals (n=7) failed initial treatment and required additional treatment courses due to persistent lesions (57%) or relapse following initial resolution (14%). 10% (n=2) required a third treatment course due to persistent/recurrent lesions. Conclusion While CL in travelers has a variety of clinical manifestations, travel history, knowledge of key clinical features, and lesion patterns can aid in early diagnosis and treatment. CL is associated with early treatment failure rate for uncertain reasons. Disclosures All Authors: No reported disclosures

Abstract Background Histoplasmosis is an endemic mycosis associated with a wide range of clinical presentations. Cardiovascular histoplasmosis (CVH) was rarely seen at our center before 2007 but has increased in frequency over the last 15 years. Herein, we describe the clinical characteristics of our recent CVH cases. Methods We identified all adults diagnosed with CVH at Mayo Clinic in Rochester, MN, between May 2007 and February 2023. Results Ten cases of CVH were identified, all of whom resided in the Midwest (Table). The majority were male, with a median age of 72 years. Five patients had prosthetic valves, two endovascular grafts, one a prosthetic valve and aortic graft, and one was a heart-kidney transplant recipient. Patients most frequently presented with prolonged night sweats, fever, and dyspnea. Cytopenias, pulmonary nodules, and splenomegaly were common laboratory and imaging findings. The diagnosis was suspected based on a positive Histoplasma antibody (100%) and/or antigen (80%) testing and confirmed by positive culture (blood 60%, explanted valve/graft 20%) and/or histopathology (60%). Identified clinical syndromes included: prosthetic valve endocarditis (PVE; 50%), native valve endocarditis (10%), mycotic aortic aneurysm (10%), aortic graft infection (10%), PVE and aortic graft infection (10%), and myocarditis (10%). Most patients received combined medical and surgical treatment (50%). Three patients (30%) received medical treatment only, including one patient with myocarditis. Two patients (20%) presented progressive clinical decline and were not considered antifungal treatment or surgical candidates. The overall mortality within one year of diagnosis was 50%. Patients with endocarditis and/or graft infection who received only medical treatment had higher mortality than those who received combined medical and surgical treatment (100% vs 20%, respectively).Table.Clinical characteristics of patients presenting with cardiovascular histoplasmosis (N=10) *Patient frequently had more than one comorbidity, symptom, laboratory or imaging finding, positive histoplasmosis testing, or affected valve. **Two patients did not receive treatment given their critical status, and were transitioned to comfort care. Conclusion CVH is being seen more frequently at our institution. One-year mortality of CVH was high, but combined medical and surgical management conferred better outcomes than medical treatment alone. We suggest a high index of suspicion of CVH in patients residing in Histoplasma endemic regions with a history of prior cardiac or vascular surgery presenting with prolonged fevers and/or new cardiomyopathy. Disclosures All Authors: No reported disclosures

Abstract Background Patent foramen ovale (PFO) can be identified in about 20-25% of the adult population and may result in variable degrees of left-to-right and right-to-left intracardiac shunting. The association between PFO and pyogenic brain abscess remains poorly understood. The current study aimed to compare the clinical characteristics and outcomes of pyogenic brain abscess in patients with and without PFO. Methods All adults with pyogenic brain abscess seen at Mayo Clinic from 1/1/2009-12/31/2021 who underwent either transesophageal echocardiography (TEE) or transthoracic echocardiography (TTE) with agitated saline shunt (bubble) study were included. Results A total of 222 patients developed pyogenic brain abscess during the study period; 148 (66.7%) patients were excluded due to unknown PFO status. Among 74 remaining patients, PFO was detected in 30 (40.5%) patients; 25 by TEE and 5 by TTE with bubble study (Figure 1). The prevalence of cryptogenic brain abscess (unable to identify the source of abscess) was significantly higher in patients with PFO as compared to those without PFO (53.3% versus 18.2%, p=0.002). Patients with PFO had a larger abscess size (25 mm [IQR 15.8-37.5] versus 15.5 mm [IQR 10.0-28.0], p=0.038). However, multiple abscesses were more common in the group without PFO (43.2% versus 20.0%, p=0.038). Additionally, patients with PFO had less documented bloodstream infection. There were no differences between other clinical characteristics and one-year, all-cause mortality between two groups. Conclusion These findings provide critical insights into the likely association between PFO and cryptogenic brain abscess; additional investigation is warranted. Disclosures Larry M. Baddour, MD, Boston Scientific: Advisor/Consultant|Roivant Sciences: Advisor/Consultant

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 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.

Background: Blastomycosis can cause severe disease with progressive respiratory failure and dissemination even in immunocompetent individuals. We sought to evaluate risk factors for severe disease and mortality using clinical and laboratory data within a large health system in an endemic area. Methods: We performed a retrospective cohort study of patients diagnosed with blastomycosis at all Mayo Clinic sites from 1 January 2004 through 31 March 2020. Diagnosis was established by culture, histopathology/cytopathology, serology, antigen testing, or PCR. Disease was categorized as mild for patients treated in the outpatient setting, moderate for hospitalized patients who did not require intensive care, and severe for patients admitted to the intensive care unit. Logistic regression was used to evaluate risk factors for severe disease. A Cox proportional hazards model was constructed to evaluate mortality. Findings: We identified 210 patients diagnosed with blastomycosis. Mean age was 51 years (range, 6–84). Most subjects were male (71.0%). Extrapulmonary disease was confirmed in 24.8%. In this cohort, 40.5% of patients had mild disease, 37.6% had moderate disease, and 21.9% had severe disease. Independent risk factors for severe disease were neutrophilia (odds ratio (OR) 3.35 (95% CI 1.53–7.35), p = 0.002) and lymphopenia (OR 3.34 (95% CI 1.59–7.03), p = 0.001). Mortality at 90 days was 11.9%. Median time from diagnosis to death was 23 days (interquartile range 8–31 days). Independent risk factors for mortality were age (OR 1.04 (95% CI 1.01–1.08), p = 0.009), neutrophilia (OR 2.84 (95% CI 1.04–7.76), p = 0.041), and lymphopenia (OR 4.50 (95% CI 1.67–12.11), p = 0.003). Blastomyces immunodiffusion had an overall sensitivity of 39.6% (95% CI 30.1–49.8). Sensitivity was higher among those who were tested 4 weeks or longer after the onset of symptoms. Urine Blastomyces antigen had a significantly higher sensitivity of 80.8% (95% CI 68.1–89.2) compared to serology. There was a trend towards higher antigen concentration in patients with severe disease. The sensitivity of PCR from respiratory specimens was 67.6% (95% CI 50.1–85.5). Conclusion: In this cohort, we did not find an association between pharmacologic immunosuppression and disease severity. Lymphopenia at diagnosis was an independent risk factor for mortality. This simple marker may aid clinicians in determining disease prognosis.