Grill, Marie

Abstract Background Coccidioidomycosis is an endemic fungal infection in the desert southwestern USA. Less than 1% of infections are complicated by coccidioidal meningitis (CM), which requires lifetime treatment, and has high morbidity. IDSA guidelines recommend high dose fluconazole (flu) as first line treatment, but up to 31% of CM patients (pts) fail flu. Guidelines have not yet articulated best subsequent therapy, but options include itraconazole (itra), voriconazole (vori), posaconazole and isavuconazole (isa). Excellent adherence to medications is imperative, and therapeutic fluconazole (flu) serum levels correlate with successful CM outcome. Many azoles are substrates of P450/CYP enzymes, and genetic alterations may influence medication levels. We have observed many CM pts who swear to adherence yet have low therapeutic azole levels. Our aim was to summarize our experience with pharmacogenomic (PGx) testing to guide treatment of CM. Methods We conducted a retrospective review of CM pts in our Coccidioidomycosis Clinic who underwent 1 of 2 targeted gene queries, either an internal 9-gene query or an external vendor 27 gene test. A PGx pharmacist interpreted results. Results From 1/1/2021 – 4/30/2023, we identified 6 pts with poorly controlled CM as manifested by repeated hospitalizations, progressively abnormal findings on lumbar puncture and/or magnetic resonance imaging of the central nervous system. Among the 6, 3 (50%) were male, 5 (83%) white, mean age 45 (28-71) years, with 34-month mean duration of illness. None were immunosuppressed. CM was complicated by strokes in 3, and hydrocephalus requiring ventriculoperitoneal shunt in 2. Five failed initial high dose flu and most had some low therapeutic levels without other medications acting as CYP inducers/inhibitors. 3 pts had the 9 gene test and 3 had the 27 gene test. Clinically relevant PGx abnormalities were identified in 5, including variants of CYP 2C19, 2C9, 3A4 and 3A5, which confer altered metabolism of vori, itra and isa, respectively. Following PGx, treatment was adjusted in 4 pts. Conclusion PGx testing is a potential adjunctive tool to avoid ineffective therapies or medication toxicity in an infection whose treatment success strongly depends on consistent therapeutic medication levels over a lifetime. Disclosures All Authors: No reported disclosures

Abstract Background Literature on the natural course of neuroinvasive West Nile virus (WNV) infection in solid organ transplant (SOT) recipients is sparse. In the setting of a 2021 WNV outbreak in Arizona, we reviewed our institution's experience with neuroinvasive WNV infection in patients with SOT. Methods We retrospectively identified SOT recipients treated for neuroinvasive WNV at Mayo Clinic in Arizona from 2007 through 2021. Clinical manifestations, disease course, and outcomes were analyzed. Results Among 24 SOT recipients with WNV infection identified during the study period, 13 infections occurred in 2021. Most patients had gastrointestinal tract symptoms and fever at disease presentation. Five patients had cognitive impairment, and 14 initially or eventually had acute flaccid paralysis. Clinically significant deterioration occurred at a median of 4 (range, 1–11) days after hospital admission. Seventeen patients (71%) were transferred to the intensive care unit, with 15 requiring mechanical ventilation. Initial cerebrospinal fluid analysis mainly demonstrated a neutrophil‐predominant pleocytosis. Almost all patients ( n = 23) were treated with intravenous immunoglobulin alone or in combination with interferon alfa‐2b. Sixteen patients had clinical improvement, 4 of whom recovered completely. Six patients died during hospitalization due to complications of neuroinvasive WNV infection. Two patients were discharged to hospice without clinical recovery. The overall 30‐day mortality rate was 36%. Conclusion Despite advances in supportive care, neuroinvasive WNV infection is associated with substantial morbidity and mortality in SOT recipients. Flaccid paralysis is an indicator of poor prognosis. image

Abstract Background Despite the increasing incidence of neuroinvasive West Nile virus (NiWNV) infection in the US, the spectrum of disease characteristics and neuroimaging findings in immunosuppressed (IS) individuals are not adequately described. We aimed to compare the clinical characteristics and outcomes of NiWNV infection in IS and immunocompetent (IC) patients. Methods We extracted relevant data from all NiWNV patients hospitalized 7/2003-10/2021 at Mayo Clinic hospitals. Cohort was inclusive of patients from the recent historic WNV outbreak in Arizona in 2021. Chi-Square or Kruskal-Wallis and logistic regression were used to compare relevant variables and determine predictors of mortality respectively. Results We included 115 patients (72 IC and 43 IS), mean age 63.5 years; neurologic syndromes included meningoencephalitis (85.2%), encephalomyelitis (8.7%) and myeloradiculitis (6.1%). Presenting symptoms were malaise (72%), fever (66%), altered mentation (64%), gastrointestinal (47%) and myalgia (35.7%). MRI brain was abnormal in 62.8% (49/78), demonstrating T2/FLAIR hyperintensities in 47.4% (brainstem, thalamus, temporal lobes), leptomeningeal enhancement (16.7%) and diffusion restriction (20.5%). Altered mental status (76.7% vs 56.9%), myalgia (44.4% vs. 20.9%), myoclonus (18.6% vs. 4.2%) and thalamic MRI T2 FLAIR abnormalities (11.4% vs 0%) were more common in IS patients. Higher CSF WBC counts were observed in IC vs IS patients (P< 0.05). Immunosuppressed patients were more likely to be treated with intravenous immunoglobulin (44.2% vs 8.3% p=< 0.001) and/or interferon therapy (32.6% vs 6.9%, p=0.0003) and had increased odds of 90-day mortality on multivariable analysis (Adjusted Odds Ratio, AOR 2.22; 95% CI 1.065-4.627, p=0.0334). In the IS subgroup, ICU admission, mechanical ventilation, and Glasgow coma scale of < 8 were associated with reduced overall survival/increased 90-day mortality (p< 0.005). Conclusion Individuals presenting in summer/fall months with the aforementioned symptoms and/or MRI abnormalities should be evaluated for NiWNV infection. Compared to the immunocompetent, immunosuppressed patients with NiWNV are at a significantly greater mortality risk. Novel and effective antiviral therapies aimed at improving outcomes are warranted. Disclosures All Authors: No reported disclosures.

Introduction: Coccidioidal meningitis (CM) is the most lethal form of disseminated coccidioidomycosis. Current guidelines recommend fluconazole as initial therapy but there has been a paucity of data regarding failure of fluconazole and optimal fluconazole dosage in the treatment of CM. We conducted this study to understand risk factors for fluconazole failure. Methods: We conducted a single-center retrospective chart review of patients diagnosed with coccidioidal meningitis between 1 January 1988 and 15 May 2021. Relevant demographic and clinical variables were collected, along with outcomes including treatment failure and death at any point. Univariate tests were conducted using the chi-squared goodness of fit test and analysis of variance. Results: Among 71 patients who began treatment for CM with fluconazole, 22 (31%) developed worsening meningitis at a median time of 206 days. Longer time from symptom onset to diagnosis of CM was a risk factor for fluconazole failure. Although the absolute failure rate of fluconazole starting dose of 400 mg daily was higher than that of 800 mg daily, the differences did not achieve statistical significance (p = 0.39). Conclusion: Fluconazole failure is not uncommon in the treatment of CM. A dose of 800 mg daily was not superior to a dose of 400 mg daily. All patients on fluconazole for CM require close monitoring.