Abstract Background CACTUS is a retrospective, matched, multicenter study comparing the efficacy of C/T and CZA for the treatment of bacteremia or pneumonia due to MDR P. aeruginosa. We previously demonstrated that treatment with C/T resulted in higher rates of clinical success compared to CZA. The objective of this analysis is to compare the day 30 Desirability of Outcome Ranking (DOOR) between matched patient pairs. Methods C/T and CZA patients were matched 1:1 within each study site based on severity of illness, infection type, and time to treatment initiation. The DOOR scale applied is described in Figure 1. Each matched pair was compared for a better ranking. The frequency of an improved DOOR for C/T compared to CZA was determined for the entire cohort (n = 210 pairs) and pneumonia subgroup (n = 175 pairs) where a DOOR of 50% would represent no difference. In addition, we measured the magnitude of DOOR differences within matched pairs. Results C/T was not associated with an improved DOOR relative to CZA in the overall cohort (53.3% (95% CI 47.2 – 59.4)) or pneumonia subgroup (54.6% (95% CI 47.9 – 61.2); Figure 1). Specifically, 37% of pairs had the same DOOR, 33% had a lower (better) DOOR with C/T, and 30% had a lower DOOR with CZA. Figure 2 shows the magnitude of DOOR differences for patient pairs. The magnitude was greater for pairs when C/T was associated with a better outcome as compared to the magnitude for pairs when CZA was associated with a better outcome. This difference was more pronounced among patients with pneumonia (Figure 3). A summary of major comparisons is shown in Figure 4. For the entire cohort, an improved DOOR by ≥2 categories within matched pairs occurred more commonly with C/T vs. CZA (p=0.03). In the subgroup of patients with pneumonia, a greater proportion of pairs showed the greatest possible difference (success without complications (DOOR=1) versus death (DOOR=5)) in favor of C/T compared to pairs in favor of CZA; 14% vs. 7%; p = 0.06. Conclusion These data demonstrate the power of matched data for analyzing DOOR endpoints. While there was no difference in the overall DOOR, the magnitude of improved outcomes consistently favored C/T over CZA and suggests clinically important differences in these agents for patients with MDR P. aeruginosa pneumonia or bacteremia. Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Samuel L. Aitken, PharmD, MPH, Basilea: Advisor/Consultant|bioMerieux: Advisor/Consultant|Melinta: Advisor/Consultant|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Beckman Coulter Inc.: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria Kate DeSear, PharmD, BCIDP, AAHIVP, FIDSA, AbbVie Inc: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|GSK: Advisor/Consultant|La Jolla (Entasis): Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant Alan E. Gross, PharmD, Becton Dickinson Co: Advisor/Consultant Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Wesley D. Kufel, Pharm.D., BCPS, BCIDP, Merck & Co.: Grant/Research Support|Shionogi, Inc: Grant/Research Support Conan MacDougall, PharmD, MAS, Merck: Grant/Research Support Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties Jeffrey C. Pearson, PharmD, inflarx: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support

Infectious disease consultation improves outcomes for S. aureus bacteremia. We developed an electronic health record alert (SABER) to automatically encourage consultation and replace manual intervention. In a pre-post evaluation, high rates of consultation and optimized patient management, shorter time to consult, and high provider-reported satisfaction were observed during SABER implementation.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

Abstract Background CACTUS is a retrospective, matched, multicenter study comparing the efficacy of C/T and CZA for treatment of bacteremia or pneumonia due to MDR P. aeruginosa. We found that treatment with C/T resulted in higher rates of clinical success compared to CZA after controlling for baseline differences between cohorts. The objective of this study is to determine the impact of patient subgroups on the overall findings. Methods C/T and CZA patients were matched 1:1 within each study site based on severity of illness, infection type, and time to treatment initiation. The primary outcome was clinical success at day 30, defined as survival, resolution of signs/symptoms of infection with the intended treatment course, and absence of recurrent infection. For subgroups of interest, the proportion with clinical success in each group was compared using an unadjusted odds ratio (OR) and 95% confidence interval. Results Among 420 cases from 28 sites, 60.95% (128/210) of C/T- and 51.9% (109/210) of CZA-treated patients experienced clinical success. Groups were overall well-balanced by matching; however, CT-treated patients were older, more likely to have immunocompromising conditions, and to receive suboptimal dosing (Table 1). After conditional logistic regression, the adjusted OR for clinical success with C/T treatment was 1.97 (95% CI: 1.11 – 3.49; P=0.02). Unadjusted OR for patient subgroups are listed in Table 2. Overall, the effect size was consistent across all subgroups. Key factors are highlighted in Figure 1. Significantly higher rates of clinical success were found for treatment with C/T compared to CZA for patients with pneumonia, SOFA ≤7, mechanical ventilation, and optimal dosing. Table 3 displays comparative 30-day mortality rates. Higher mortality rates were identified in both C/T- and CZA-treated patients who were critically-ill, received suboptimal dosing, and were treated within 72 hours of index culture (Table 3); rates did not vary by treatment. Conclusion The consistency of the results in this subgroup analysis of CACTUS reinforces the primary finding of higher rates of clinical success for patients with MDR P. aeruginosa pneumonia or bacteremia treated with C/T compared to CZA. Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Samuel L. Aitken, PharmD, MPH, Basilea: Advisor/Consultant|bioMerieux: Advisor/Consultant|Melinta: Advisor/Consultant|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Beckman Coulter Inc.: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria Kate DeSear, PharmD, BCIDP, AAHIVP, FIDSA, AbbVie Inc: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|GSK: Advisor/Consultant|La Jolla (Entasis): Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant Alan E. Gross, PharmD, Becton Dickinson Co: Advisor/Consultant Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Wesley D. Kufel, Pharm.D., BCPS, BCIDP, Merck & Co.: Grant/Research Support|Shionogi, Inc: Grant/Research Support Conan MacDougall, PharmD, MAS, Merck: Grant/Research Support Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties Jeffrey C. Pearson, PharmD, inflarx: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support

Abstract Background Comparative pre-clinical studies examining humanized pharmacokinetic/pharmacodynamic (PK/PD) exposures of triazoles against A. fumigatus (AF), including clinical wild-type and cyp51 mutants, is lacking. These studies are important to set rational clinical breakpoints, predict clinical outcomes, and provide data to guide drug and dosing choice to optimize efficacy. The aim of this study was to compare target AUC/MIC exposures in the context of expected humanized exposures for posaconazole (P) and isavuconazole (I) against AF. Posaconazole AUC/MIC and Treatment Response in the Murine IPA Model Relationship between posaconazole free drug AUC/MIC and treatment response in the animal model. The dashed horizontal line is net stasis from the start of therapy. Overlaid with vertical lines are the expected humanized AUC/MIC exposures for various MIC values (range 0.25-2 mg/L). Organisms with MIC values of ≤1 mg/L would fall in the net cidal (i.e. log kill) area on the exposure response curve based on humanized AUC/MIC exposures. Methods A neutropenic murine model of IPA with 7 AF clinical strains (2 WT, 5 cyp51 mutants) were utilized. MICs were determined by CLSI methods. Plasma PK were determined after single oral doses (4 dose levels) of P or I at 7 time points. Infection was induced by nasal aspiration of 50ul of a 1x10^7 conidia/ml inoculum in anesthetized mice. Treatment doses in the mouse incorporated humanized AUC exposures to examine the PK/PD relationship in the context of MIC variation within clinical strains. The duration was 96 hours. Drug efficacy was determined by qPCR of AF DNA from lyophilized lung tissue. AUC/MIC and treatment effect was modelled using the sigmoid Emax equation. Isavuconazole AUC/MIC and Treatment Response in the Murine IPA Model Relationship between isavuconazole free drug AUC/MIC and treatment response in the animal model. The dashed horizontal line is net stasis from the start of therapy. Overlaid with vertical lines are the expected humanized AUC/MIC exposures for various MIC values (range 0.25-2 mg/L). Organisms with MIC values of <0.5 mg/L would fall in the net cidal (i.e. log kill) area on the exposure response curve based on humanized AUC/MIC exposures. Results P and I MIC ranged from 0.25-2 mg/L and 0.5-4 mg/L, respectively. The 96h AUC for both drugs was linear (R2 > 0.99). Increasing dose was associated with increased effect. A sigmoidal relationship between AUC/MIC and treatment effect was noted for both drugs. The median 96h free drug AUC/MIC target for net stasis was 1.61 for P and 4.18 for I (P = 0.001). The PK/PD curves for the animal model are shown in the figures. Overlaid are the expected humanized AUC/MIC exposures for various common MIC values. Conclusion P had comparatively lower free AUC/MIC target exposures than I. Moreover, P had more potency based on expected humanized exposures. The humanized AUC/MIC exposures for P would consistently fall in the cidal activity of the efficacy curve for strains with P MIC ≤ 1 mg/L; however, I was more heterogenous and humanized AUC/MIC exposures in the cidal portion of curve occur only at MIC values < 0.5 mg/L. This data will be integrated with human clinical PK variability, MIC distributions, and clinical outcome data based on MIC for target attainment analysis and breakpoint determination. Disclosures Brian D. VanScoy, B.S., Achaogen Inc.: Grant/Research Support|Adagio Therapeutics, Inc.: Grant/Research Support|AiCurtis Anti-infective Cures AG: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|BioFire Diagnostics, LLC.: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Cumberland Pharmaceuticals Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Excalibur Pharmaceuticals Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Global Antibiotic Research and Development Partnership: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: Grant/Research Support|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novobiotic Pharmaceuticals LLC: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer Inc: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100 Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences Inc.: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co: Grant/Research Support|Theravance: Grant/Research Support|University of Wisconsin: Grant/Research Support|US Food and Drug Administration: Grant/Research Support|UT Southwestern: Grant/Research Support|ValanBio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Zogenix International: Grant/Research Support Catharine Vincent, Ph.D., Achaogen Inc.: Grant/Research Support|Adagio Therapeutics, Inc.: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|BioFire Diagnostics, LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Cumberland Pharmaceuticals Inc.: Grant/Research Support|Entasis Therapeutics Inc.: Grant/Research Support|Excalibur Pharmaceuticals Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genetech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Global Antibiotic Research and Development Partnership: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Employee|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech Health LYT 100 Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences Inc.: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|University of Wisconsin: Grant/Research Support|US Food and Drug Administration: Grant/Research Support|ValanBio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Zogenix International: Grant/Research Support

Recombinant protein production is pivotal in molecular biology, enabling profound insights into cellular processes through biophysical, biochemical, and structural analyses of the purified samples. The demand for substantial biomolecule quantities often presents challenges, particularly for eukaryotic proteins. Escherichia coli expression systems have evolved to address these issues, offering advanced features such as solubility tags, posttranslational modification capabilities, and modular plasmid libraries. Nevertheless, existing tools are often complex, which limits their accessibility and necessitates streamlined systems for rapid screening under standardized conditions. Based on the Golden Gate cloning method, we have developed a simple 'one-pot' approach for the generation of expression constructs using strategically chosen tags like hexahistidine, SUMO, MBP, GST, and GB1 to enhance solubility and expression. Tags are removable via TEV protease cleavage, and the system allows visual cloning verification through mScarlet fluorescence. We provide a comprehensive protocol encompassing oligonucleotide design, cloning, expression, Ni-NTA affinity chromatography, and size-exclusion chromatography. This method therefore streamlines prokaryotic and eukaryotic protein production, rendering it accessible to standard molecular biology laboratories with basic protein biochemical equipment.

Per the Pan American Health Organization/World Health Organization, Oropouche virus (OROV) is a reemerging arbovirus that poses a yet undetermined degree of threat to the United States, with outbreaks reported in the Caribbean and South America, including new areas of spread, since the end of 2023 and, at this time, there exists no vaccine or disease-specific treatment. Here we describe the presentation and diagnosis of a neuroinvasive case of OROV, the first documented case of OROV in Wisconsin, the first documented case in the United States in 2025, and the first documented US case associated with travel to Panama.

Abstract Background Ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) are front-line agents for treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa; however, real-world comparative-effectiveness data are lacking. Methods CACTUS is a retrospective, matched, multicenter study to compare the efficacy of CT and CZA among patients with bacteremia or pneumonia due to MDR P. aeruginosa. CT and CZA patients were matched 1:1 within each study site by the presence/absence of septic shock/severe sepsis, infection site, and time to treatment initiation. The primary outcome was clinical success at day 30 defined as survival, resolution of signs/symptoms with the intended treatment course, and absence of recurrent infections. Patients with cystic fibrosis or COVID-19 infection within 90 days were excluded. Results 234 patients were included from 20 sites. Patient demographics, severity of illness, infection types, and treatment durations were similar for patients treated with CT or CZA (Table 1). The overall median age was 61 years, 61% were male, and the median Charlson score was 5. At study drug initiation, 77% of patients were in the ICU, 67% received mechanical ventilation and the median SOFA score was 7. 79% of patients were treated for pneumonia; 72% of which occurred in ventilated patients. The median time from index culture to treatment initiation was 72 hours in both groups; CT patients were more likely to receive a prolonged infusion of ≥3 hours (36% vs 19%; P=0.005). Clinical success occurred in 62% and 55% of patients receiving CT and CZA, respectively (P=0.35; Table 1). Corresponding rates of success for pneumonia were 63% and 52%, respectively (P=0.13; Figure 1). All-cause, 30-day mortality rate was 20% and 19%, respectively. Microbiologic failures, recurrent infections, and development of resistance within 90 days were similar between groups. Time to a composite endpoint of recurrent infection or death within 90 days was similar between groups in the overall analysis and the subgroup of patients with pneumonia (Figure 2). Conclusion In this interim analysis of the CACTUS study, patients treated with CT and CZA had similar clinical outcomes. We plan to continue enrollment up to 420 patients to detect if any differences exist in the efficacy of CT and CZA for MDR P. aeruginosa infections. Disclosures Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Lilian M. Abbo, MD, MBA, Ferring: Advisor/Consultant|Pfizer: Advisor/Consultant|Regeneron: Grant/Research Support|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Roche: Advisor/Consultant Kimberly C. Claeys, PharmD, Abbvie: Advisor/Consultant|bioMérieux Inc.: Advisor/Consultant|bioMérieux Inc.: Speaker|La Jolla Pharmaceuticals: Advisor/Consultant|Melinta Therapeutics: Advisor/Consultant Jason C. Gallagher, PharmD, Entasis: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Emily L. Heil, PharmD, MS, Wolters Kluwer-LexiComp: Advisor/Consultant Wesley D. Kufel, PharmD, BCPS, BCIDP, AAHIVP, Merck and Co: Grant/Research Support Amy Mathers, MD, D(ABMM), Merck: Advisor/Consultant Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Honoraria|La Jolla (Entasis): Advisor/Consultant|LabSimply: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Christopher Polk, MD, ViiVHealthcare: Job change to work for ViiV as Medical Director Michael J. Satlin, MD, AbbVie: IDMC member|Biomerieux: Grant/Research Support|Merck: Grant/Research Support|SNIPRBiome: Grant/Research Support Michael Veve, PharmD, MPH, National Institutes of Health: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant

SF001 is a next-generation polyene antifungal drug in development, designed to have increased specificity to fungal ergosterol, which is absent in humans, and decreased binding to cholesterol. SF001 demonstrates long-acting, potent, broad-spectrum fungicidal activity. The goal of the current study was to determine the pharmacodynamic index and target of SF001 in an immunocompromised mouse model of invasive pulmonary aspergillosis against six Aspergillus fumigatus isolates. Minimum inhibitory concentration (MIC) values ranged from 0.5 to 2.0 mg/L. Plasma and epithelial lining fluid (ELF) pharmacokinetics were performed following single intraperitoneal doses of 1, 4, 16, and 64 mg/kg. Treatment efficacy was assessed with each of the six fungal isolates using daily doses of SF001 ranging from 0.25 to 64 mg/kg/day over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24-h exposure-response relationships for both plasma and ELF area under the concentration/MIC and C-max/MIC ratios were strong and relatively similar [coefficient of determination (R-2) = 0.74-0.75). Exposure-response relationships included a median plasma 24-h C-max/MIC target for stasis and 1-log kill endpoint of 0.5 and 0.6, respectively. The present studies demonstrated in vitro and in vivo SF001 potency against A. fumigatus. These results have potential relevance for SF001 clinical dose selection and evaluation of susceptibility breakpoints.

PURPOSE:The fluoroquinolone restriction for the prevention of Clostridioides difficile infection (FIRST) trial is a multisite clinical study in which sites carry out a preauthorization process via electronic health record-based best-practice alert (BPA) to optimize the use of fluoroquinolone antibiotics in acute care settings. Our research team worked closely with clinical implementation coordinators to facilitate the dissemination and implementation of this evidence-based intervention. Clinical implementation coordinators within the antibiotic stewardship team (AST) played a pivotal role in the implementation process; however, considerable research is needed to further understand their role. In this study, we aimed to (1) describe the roles and responsibilities of clinical implementation coordinators within ASTs and (2) identify facilitators and barriers coordinators experienced within the implementation process. METHODS:We conducted a directed content analysis of semistructured interviews, implementation diaries, and check-in meetings utilizing the conceptual framework of middle managers' roles in innovation implementation in healthcare from Urquhart et al. RESULTS:Clinical implementation coordinators performed a variety of roles vital to the implementation's success, including gathering and compiling information for BPA design, preparing staff, organizing meetings, connecting relevant stakeholders, evaluating clinical efficacy, and participating in the innovation as clinicians. Coordinators identified organizational staffing models and COVID-19 interruptions as the main barriers. Facilitators included AST empowerment, positive relationships with staff and oversight/governance committees, and using diverse implementation strategies. CONCLUSION:When implementing healthcare innovations, clinical implementation coordinators facilitated the implementation process through their roles and responsibilities and acted as strategic partners in improving the adoption and sustainability of a fluoroquinolone preauthorization protocol.

Background: Despite high negative predictive values (NPVs) seen with methicillin-resistant Staphylococcus aureus (MRSA) nares polymerase chain reaction (PCR) assays, utilization of both respiratory sample Gram stain and MRSA nares PCR in patients with pneumonia may contribute to overuse of laboratory resources. The purpose of this study was to evaluate if a Gram stain demonstrating no Gram-positive organisms from a respiratory sample is sufficient to allow for de-escalation of vancomycin therapy. Methods: This single center study retrospectively identified intensive care unit (ICU) patients started on vancomycin for presumed pneumonia at University of Wisconsin (UW) Health in Madison, WI between August 2022 and March 2023. Patients with respiratory sample demonstrating no Gram-positives on Gram stain met inclusion criteria if the sample was ordered within 24 h of vancomycin initiation. The primary outcome was NPV of respiratory sample Gram stain demonstrating no Gram-positive organisms with respect to MRSA detection of the respiratory culture. Secondary outcomes included the NPV of combined MRSA nares PCR plus respiratory sample Gram stain, and difference in time to event in patients that had both a respiratory sample and MRSA nares PCR ordered. Results: A total of 370 patients were screened for study eligibility; of which 99 patients met inclusion criteria. NPV of respiratory sample Gram stain was 99% for MRSA culture. The combined NPV of respiratory sample Gram stain plus MRSA nares PCR was 98.9% for MRSA culture (n = 88). Respiratory sample was ordered 2.3 h faster compared to MRSA nares PCR (4.3 vs 6.6 h, P = .036). Respiratory sample Gram stain resulted 4.5 h faster compared to MRSA nares PCR (10.7 vs 15.2 h, P = .002). Conclusion: Respiratory sample Gram stains demonstrating no Gram-positive organisms may be used to de-escalate vancomycin and deprioritize the use of MRSA nares PCR.

Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Nystatin, a polyene, is one of the oldest antifungal drugs with wide in vitro potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using in vivo invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including Aspergillus fumigatus, Candida albicans, Candida auris, and Candida glabrata. For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for A. fumigatus studies. For all Candida studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate Aspergillus in the lung and colony forming units (CFU) counts for Candida in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration (Cmax)/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for C. glabrata. Increasing exposures were needed for same outcome for C. auris at 18.7, C. albicans at 29.3, and A. fumigatus at 102.4. Cmax/MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. Cmax/MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.

Abstract Background Cephalexin (LEX), cefuroxime axetil (CXM), and cefpodoxime (CPD) are common oral cephalosporins used to treat gram-positive and gram-negative infections. However, there is a paucity of PK/PD analyses to inform optimal dosing regimens, which drug may be preferred for a particular organism, and the susceptibility testing interpretive criteria (STIC) that may apply to help clinicians in their selection. Methods 5 E. coli (EC) and 5 S. aureus (SA) clinical strains were used. MICs were determined by CLSI methods. Pharmacokinetics of LEX, CXM, and CPD were performed in mice at 10, 40, 160, and 320 mg/kg. Dose-ranging efficacy studies were performed against all strains (dose range 2.5-320 mg/kg/4h). Treatment outcome was determined by organism burden in the thighs (CFU) at the end of each experiment (24 h). The dose-response (D-R) data was analyzed using the Emax Hill equation. Data was fit to the PK/PD index time above MIC (T >MIC) for free drug concentrations. Static and cidal target exposures were calculated for each strain, and targets compared by One Way ANOVA. Results EC MIC ranges: LEX 4-64mg/L, CXM 1-8 mg/L, CPD 0.125-8 mg/L. SA MIC ranges: LEX 2-16 mg/L, CXM 0.5-2 mg/L, CPD 2-8 mg/L. All three drugs performed similarly well against SA with relatively steep D-R curves and achieving >1-log kill against 5 of 5 strains. For EC studies, LEX demonstrated a flat, more muted effect with only 2 of 5 strains achieving a 1-log kill. Comparatively, CXM and CPD demonstrated a steeper, more potent D-R curve against EC with a >1-log kill against 4 of 5 strains for CXM and 5 of 5 for CPD. The PK/PD index T >MIC fit the treatment efficacy data well (R2 0.66-0.91). Summary statistics for PK/PD analyses are shown in Figure. Conclusion Oral 1st-3rd generation cephalosporins exhibited efficacy against SA and EC in the mouse thigh infection model. Stasis and 1-log kill targets for the three drugs against SA were 25-35% and 35-45% T >MIC, respectively. Lower targets were noted for 1st generation LEX. PK/PD targets for stasis and 1-log kill for EC were 40-50% and 45-75% T >MIC, respectively. Lower targets were noted for 2nd generation CXM. These studies will be integral in evaluation of PK/PD target attainment by integrating human population PK for standard dosing regimens of each drug and MIC distribution data. Disclosures Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Catharine Vincent, Ph.D., Adagio Therapeutics: Grant/Research Support|Albany Medical College: Grant/Research Support|Amplyx Pharmaceuticals: Grant/Research Support|AN2: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics: Grant/Research Support|B. Braun Medical: Grant/Research Support|Basilea: Grant/Research Support|BioFire Diagnostics: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Cidara: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone: Grant/Research Support|CXC: Grant/Research Support|Debiopharma International SA: Grant/Research Support|Entasis: Grant/Research Support|Genentech: Grant/Research Support|GSK: Grant/Research Support|Hoffman-La Roche: Grant/Research Support|Inotrem: Grant/Research Support|Insmed: Grant/Research Support|Iterum Therapeutics: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|KBP Biosciences: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma: Grant/Research Support|Melinta: Grant/Research Support|Menarini Ricerche: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|Univ of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics: Grant/Research Support|VenatoRx: Grant/Research Support Brian D. VanScoy, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support David Andes, MD, Astellas: Advisor/Consultant|Sfunga: Advisor/Consultant

Background: The FIRST Trial is a 5-year study funded by the Agency for Healthcare Research and Quality. Our investigation is situated within a more extensive study to restrict fluoroquinolone antibiotics by requiring providers to obtain authorization from an infectious disease physician before prescribing fluoroquinolones. Our research team is performing a systematic evaluation to identify organizational characteristics and influencers of the fluoroquinolone preprescription authorization implementation process to understand variables that may facilitate or hinder implementation success. Methods: To address this critical gap, we present a qualitative analysis from our ongoing, multisite research project aimed at systematically assessing the adoption of an antimicrobial stewardship intervention in the form of an EHR-integrated best-practice alert (BPA) at each site to identify work system factors that impact uptake and variability in the implementation of the BPA at each location. The evaluation provides a detailed explanation of activities through the implementation process (eg, before implementation, during implementation, and after implementation) to assess how an organization effectively negotiates the phases and transitions, ultimately influencing the impact of the intervention. We have used a contextual determinant framework (CFIR) that has enabled us to perform a systematic and comprehensive exploration and identification of potential explanatory themes or variables to shed light on the complex social phenomenon of implementation. Results: Participants who will be a part of our poster presentation will learn about implementing a BPA, the potential barriers to implementation, and strategies for overcoming these barriers. Stakeholders within our study include site coordinators, medical doctors, nurses, pharmacists, and clinical informaticists. Our analysis synthesizes their experiences implementing and sustaining this evidence-based antimicrobial stewardship intervention. It includes (1) a detailed description of the process of change, (2) work-system factors (eg, inner setting and outer setting) that they believe influenced the success of the intervention, (3) barriers and facilitators (eg, CFIR constructs) within the implementation process; and (4) description of how these could have influenced the outcomes of interest (eg, implementation and intervention effectiveness). Conclusions: Our research is expected to advance patient safety research and initiatives by providing a more robust approach to performing systematic intervention evaluations. By outlining stakeholders’ experiences within our study, implementation leaders within healthcare systems will utilize our findings to aid them in their design and implementation process when designing and implementing similar types of healthcare interventions. Disclosures: None

This cohort study examines the rates of neutropenic fever–associated admissions and outpatient antibiotic use among patients with cancer receiving chemotherapy before and during the COVID-19 pandemic.

Acinetobacter baumannii- Acinetobacter calcoaceticus complex (referred to herein as A. baumannii ) treatment guidelines contain numerous older antimicrobial agents with susceptibility test interpretive criteria (STIC, also known as susceptibility breakpoints) set using only epidemiological data. We utilized a combination of in vitro surveillance data, preclinical murine thigh and lung infection models, population pharmacokinetics, simulation, and pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses to evaluate A. baumannii STIC for four commonly recommended antimicrobials from different classes (amikacin, ceftazidime, ciprofloxacin, and minocycline).