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Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson’s disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS does not provide functional information on the identified candidate loci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses in Drosophila to discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonal in silico methods and found to be functionally related to PD-associated pathways (i.e. endolysosome). We then mimicked these TWAS-predicted transcriptomic alterations in a Drosophila PD model and discovered that 50 candidates can modulate α-Synuclein(α-Syn)-induced neurodegeneration, allowing us to nominate new genes in previously known PD loci. We also uncovered additional novel PD candidate genes within GWAS suggestive loci (e.g. TTC19, ADORA2B, LZTS3, NRBP1, HN1L), which are also supported by clinical and functional evidence. These findings deepen our understanding of PD, and support applying our integrative approach to other complex trait disorders.

Background Area under the curve (AUC)-guided monitoring of vancomycin for the treatment of Staphylococcus aureus (SA) infections demonstrates reduced rates of nephrotoxicity in clinical studies. Many institutions utilize AUC-guided dosing for all patients receiving vancomycin, despite extrapolated AUC goals for non-SA infections. We sought to define risk factors for vancomycin-induced kidney injury (VIKI) in non-SA infections. Methods This was a retrospective, single-center, case-control study evaluating risk factors associated with VIKI in hospitalized patients receiving AUC-guided dosing for non-SA infections from 2/2019-10/2021. Cases were defined as patients with non-SA infections who received >72 hours of vancomycin and had >1 observed vancomycin concentration with a corresponding AUC calculated who developed VIKI within 24 hours of vancomycin discontinuation. Controls had to meet all case criteria but did not have VIKI. Univariate and multivariable analyses were used to identify risk factors associated with VIKI. Multivariable analyses were conducted using the Optimal Data Analysis package for R. Results Twenty-three cases and 48 controls were included. Leading indications were bloodstream (52.1%) and severe skin/skin structure (46.5%) infections. Isolated pathogens from culture included coagulase-negative Staphylococcus (49.3%) and Streptococcus spp. (43.7%). The majority of vancomycin AUCs (52%) were collected within 24-48 hours of initiation. The median first and second AUCs were higher in cases vs. controls [429 vs. 385 mg*hr/L, p=0.013; and 573 vs. 429 mg*hr/L, p=0.021], respectively. Most patients (75%) experienced AKI within 72 hours of vancomycin initiation, with a median time to AKI of 5 days (IQR 2.5-7). Risk factors associated with AKI included any AUC exceeding 515 mg*hr/L, infection caused by pathogens other than Streptococcus spp., and non-bacteremia indications. Patients with AUCs exceeding 515 mg*hr/L had 3.7-fold greater odds of VIKI (p=0.017). Conclusion We found that higher AUCs increased the risk of VIKI in non-SA infections and that the risk of VIKI varied by vancomycin indication. Our findings agree with previous studies in SA indicating that vancomycin AUC should not generally exceed 515 mg*hr/L. Disclosures Nathaniel J. Rhodes, PharmD MS, Paratek: Grant/Research Support|Third Pole Therapeutics: Advisor/Consultant.

Background Obtaining scarce antimicrobials used to treat infrequently encountered infections such as malaria have posed a challenge to clinicians and health systems. Due to the rare occurrence of these infections, maintaining adequate, readily available supply for emergent need is challenging, and a lack of clear procurement processes from regional storage sites may contribute to delays in care. In March 2021, artesunate became commercially available for the treatment of severe malaria, a disease for which prompt initiation of therapy is paramount. To improve access to this and other critical but seldom used medications, a centralized storage and allocation process was established throughout our 10-hospital health system. We aim to describe the structure of this program which may serve as a model for other institutions to expedite and streamline access to these lifesaving therapies. Tracking document for therapy supply management. Methods In May 2021, a centralized process was created to track and store rare anti-infective medications for uncommon infections, including those caused by tropical, parasitic, and mycobacterial pathogens (Table 1). Supply is monitored and maintained by clinical pharmacists monthly to ensure adequate courses are available. When needed for a specific patient, infectious diseases physicians and pharmacists recommend therapy which triggers a request to the central pharmacy. Results Medications are stored at our large academic medical center (AMC), which manages these cases more routinely compared to other sites. Community hospitals within the health system are able to contact the AMC for prompt distribution of these medications when needed. Since its inception, we have deployed rare use anti-infective medications to partner facilities twice for severe malaria cases, which resulted in expedited receipt of therapy for critically ill patients. The time from therapy recommendation to medication administration was reduced from 12–24 hours to 2–6 hours. Conclusion This centralized rare anti-infective medication process expedites and streamlines access for critical therapeutic agents to ensure they are readily available when needed by limiting procurement/storage concerns. This model may be used as a framework for other medications for which timely administration, but rare use, is critical to patient care. Disclosures All Authors: No reported disclosures.

Background Up to 15% of hospitalized patients report a penicillin allergy, but most can tolerate a β-lactam (BL). Use of second-line non-BL antibiotics poses untoward health consequences. Assessing for true penicillin allergies includes penicillin skin testing (PST) and a direct amoxicillin challenge, each with their own limitations in hospitalized patients. For inpatients, a graded challenge (GC) with the desired BL offers a streamlined approach for many who could benefit from a first-line BL agent. In 2019, a hospital-wide BL Allergy Assessment and Clinical Pathway was implemented, including a BL GC protocol for low-risk patients. This study aimed to assess the safety of the GC procedure in hospitalized patients. Methods A retrospective, observational cohort study of adult inpatients who completed a GC procedure between Sept 2019 – Sept 2021 was conducted. Primary objective: determine the incidence of a significant hypersensitivity reaction from a BL GC. Secondary objectives: 1) determine the incidence of a non-hypersensitivity reaction and 2) identify antimicrobial stewardship interventions in those tolerant to a BL GC (e.g. antibiotic switch to a BL with completion of treatment course and de-labeling of penicillin allergy). Results Fifty-one patients completed a GC procedure. Most (78%) had a reported allergy to penicillin vs. other BL antibiotics. Reported allergic reactions stratified by risk for a serious hypersensitivity episode were: low/reaction > 10 yrs ago – 33%; moderate-high/reaction > 10 yrs ago – 47%, and moderate-high/reaction < 5 yrs ago – 19.6%. A PST prior to a GC was performed in 75% of patients. Common GC agents included amoxicillin-clavulanate (16%), amoxicillin (12%) and ceftriaxone (12%). One patient experienced a hypersensitivity reaction managed with diphenhydramine and another patient had a non-hypersensitivity reaction. Both cases were non-life-threatening. Of the 49 patients who tolerated a GC, 76% were switched to a BL with completion of treatment course, and 84% of documented penicillin allergies were de-labeled or clarified in the electronic medical record. Conclusion The GC procedure in our hospitalized patients was generally well tolerated including those with an allergy history concerning for a moderate-high risk hypersensitivity reaction. Disclosures Nathaniel J. Rhodes, PharmD, MSc, American Academy of Colleges of Pharmacy: Grant/Research Support|Paratek: Grant/Research Support|Third Pole Therapeutics: 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.

Purpose The coronavirus disease 2019 (COVID-19) pandemic has impacted the activities of healthcare workers, including postgraduate pharmacy trainees. Quality training experiences must be maintained to produce competent pharmacy practitioners and maintain program standards. Methods A cross-sectional survey of postgraduate pharmacy trainees in the United States was conducted to evaluate training experience changes and assess perceived impacts on residents and fellows following the COVID-19 pandemic’s onset. Results From June 4 through June 22, 2020, 511 pharmacy trainees in 46 states completed the survey. Participants’ median age was 26 (interquartile range [IQR], 25-28) years, with included responses from postgraduate year 1 residents (54% of sample), postgraduate year 2 residents (40%), and postgraduate fellows (6%). Compared to experiences prior to the onset of the COVID-19 pandemic, fewer trainees conducted direct patient care (38.5% vs 91.4%, P < 0.001), more worked from home (31.7% vs 1.6%, P < 0.001), and less time was spent with preceptors per day (2 [IQR, 2-6] hours vs 4 [IQR, 1-4] hours, P < 0.001). Sixty-five percent of respondents reported experiencing changes in their training program, 39% reported being asked to work in areas outside of their routine training experience, and 89% stated their training shifted to focus on COVID-19 to some degree. Most respondents perceived either major (9.6%) or minor (52.0%) worsening in quality of experience, with major and minor improvement in quality of experience reported by 5.5% and 8.4% of respondents, respectively. Conclusion Pharmacy resident/fellow experiences were perceived to have been extensively impacted by the COVID-19 pandemic in varying ways. Our findings describe shifts in postgraduate training and may aid in the development of best practices for optimizing trainee experiences in future crises.

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Background Nosocomial acquisition of vancomycin-resistant Enterococcus (VRE) is one of the most challenging problems in healthcare. As Enterococcus isolates are increasingly resistant to vancomycin, clinicians now rely on alternative antimicrobial therapies including linezolid and daptomycin (DAP) to treat infections. For multidrug-resistant (MDR) VRE, combination therapy with beta-lactams and daptomycin has been shown to be effective. Methods Following initiation of empiric DAP and ceftaroline (CPT) for an MDR E. faecium bloodstream infection (VRE_001), we aimed to determine if there existed in vitro synergy between both agents that supported their clinical use. Combination synergy testing was performed using E-test strips and minimal inhibitory concentrations (MICs) were read at 24 hours. For whole genome sequence-based analysis (WGS), genomic DNA from VRE_001 was used for both short read (Illumina MiSeq) and long-read sequencing (MinION, Nanopore). The complete genome was assembled and the NCBI AMRFinderPlus program used to identify known resistance mechanisms. Results Original MICs of VRE_001 from the clinical microbiology laboratory at Northwestern Memorial revealed an MDR E. faecium (Table 1). Combination synergy testing in the experimental laboratory revealed only modest amounts of synergy between CPT and DAP (Table 2). Following WGS, VRE_001 was identified as an ST-584 E. faecium with a 3.2 Mbp genome, including a single chromosome and five plasmids. WGS analysis revealed several mechanisms of antimicrobial resistance (Table 3) genetically supporting the observed MDR-DLVRE phenotype. Conclusion Our investigational antimicrobial testing allowed for real-time in vitro analysis of synergistic MICs in a case of DLVRE bacteremia. Despite the fact that in vitro testing of CPT and DAP did not support the clinical usage of combination antimicrobial therapy, the patient cleared their blood cultures. WGS of VRE_001 revealed a plethora of antimicrobial resistance mechanisms including three mutations that explain high levels of DAP resistance. Synergy testing is not routinely available in most clinical laboratories, but rapid implementation of investigational MIC testing paired with genomic analysis may one day successfully support real-time clinical decision making. Disclosures All Authors: No reported disclosures

Background Pseudomonas aeruginosa (PsA) is an infrequent pathogen associated with poor outcomes in community-acquired pneumonia (CAP). Identifying patients at high and low-risk for PsA in CAP is necessary to reduce inappropriate and overly broad-spectrum antibiotic use. We evaluated the distribution of risk-factors in hospitalized CAP patients with and without PsA infection. Methods Design: retrospective, single-center, case–control study. Inclusion: hospitalized CAP patients admitted to the general medicine wards between January 1, 2014 and May 29, 2018. Exclusion: cystic fibrosis, ≥ 3 admissions within 30 days, CAP requiring ICU admission, and death within 48 hours of admission. Case patients had PsA in respiratory or blood cultures during the index CAP admission. Controls were randomly selected targeting a 3:1 ratio. Comorbidities, pneumonia severity index, and m-APACHE II were assessed. Gram-negative risk factors defined by Shindo et al. 2013 (PMID: 23855620) and validated by Kobayashi et al. (2018; PMID: 30349327) were scored for each patient. Stepwise logistic regression was used to identify covariates that distinguished cases from controls at a P < 0.2; these were then used to generate propensity weights (i.e., inverse-probability conditioned on covariates). Unadjusted and adjusted odds ratios for case status were estimated using logistic regression according to: the total number of risk factors present and threshold values, respectively. All analyses were conducted using IC Stata (v.14.2). Results 54 cases and 152 controls were included. The distribution of the patient-specific sum of risk factors for PsA is shown in Figure 1. The univariate OR for case status was 4.29 (95% CI:1.55–11.9) at n = 3 risk factors, which was similar after propensity weight adjustment [aOR = 4.64 (95% CI: 1.32–16.3)]. The univariate OR of case status was 2.98 among patients with ≥ 3 risk factors (95% CI: 1.34–6.62), which was similar after propensity weight adjustment [aOR = 2.8 (95% CI: 1.02–7.72)], and correct classification was 73.8%. Conclusion At a threshold of ≥ 3 PsA risk factors, cases and controls were well classified, even after adjusting for propensity weights. The impact of patient-specific PsA risk-stratification on CAP outcomes and appropriate antibiotic use should be evaluated. Disclosures All authors: No reported disclosures.