475. Does Metabolite Matter? Defining Target Itraconazole and Hydroxy-itraconazole Serum Levels for Blastomycosis

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 > 1.0 mcg/mL is guideline recommended for treatment of invasive fungal infections; conversely, some experts suggest targeting a parent compound level alone > 1.0 mcg/mL. This study aims to compare clinical outcomes and adverse drug reactions (ADRs) of combined itraconazole and hydroxy-itraconazole levels > 1.0 mcg/mL versus itraconazole parent compound alone > 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 > 1.0 mcg/mL versus itraconazole parent compound > 1.0 mcg/mL for > 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 > 1.0, 32 = itraconazole parent alone > 1.0, 12 = 75% of all levels < 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 > 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 > 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.