Stevens, Ryan W.

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.

Abstract Objective: Antibiotics are frequently prescribed for acute sinusitis despite national guidelines recommending antibiotics only if specific symptom criteria are met. We aimed to define the proportion of acute sinusitis encounters meeting criteria for antibiotic prescribing, characterize prescribing practices, and identify factors associated with guideline-discordant prescribing. Design: This retrospective cohort study included 1,000 randomly selected adult ambulatory encounters with a primary diagnosis of acute sinusitis between January 1, 2024 and March 31, 2024. Encounter notes were reviewed for appropriate antibiotic prescribing criteria as per national guidelines. Encounters were evaluated for drug selection and duration concordance based on local guidelines. A multivariable logistic regression analysis was performed to identify predictors of inappropriate antibiotic prescribing. Setting: Emergency departments, urgent care centers, and primary care clinics. Results: Antibiotic prescribing criteria were met for 67.6% of included encounters. Antibiotics were prescribed in 93.5% of encounters that met prescribing criteria, and 80.2% of encounters that did not. Both drug selection and duration were guideline-concordant in 49.2% of total encounters. On multivariable analysis, predictors of inappropriate antibiotic prescribing included cough (OR 2.15, 95% CI 1.08–4.29; P = 0.03) and symptom duration between 7 and 9 days (compared to <6 days; OR 7.70, 95% CI 3.24–18.31; P < 0.001). Electronic encounters were associated with lower odds of prescribing compared to in-person encounters (OR 0.03, 95% CI 0.01–0.09; P < 0.001). Conclusions: Most encounters for acute sinusitis result in an antibiotic prescription, despite prescribing criteria not being met. These findings may aid antimicrobial stewardship programs in benchmarking and optimizing antibiotic prescribing for acute sinusitis.