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Background Beta-lactam therapeutic drug monitoring (BL TDM; drug level testing) can facilitate improved outcomes in critically ill patients. Yet less than 20% of hospitals have implemented BL TDM. The purpose of this study was to characterize provider perceptions and key considerations for successful implementation of BL TDM. Methods This was a sequential mixed methods study from 2020 to 2021 of stakeholders at three academic medical centers with varying degrees of BL TDM implementation - Mayo Clinic (BL TDM not implemented), University of Florida Health Shands (partially implemented), and Royal Brisbane and Women’s Hospital (fully implemented). Stakeholders completed a survey to characterize their knowledge, perceptions, and experience with BL TDM. A diverse group of 30 respondents were then purposively sampled for semi-structured interviews. Results from the two strands were integrated, themes were identified, and findings were situated within implementation science frameworks. Results Among the 138 survey respondents (22% response rate), the majority were physicians (38%) and pharmacists (33%). 71% practiced in critical care and 21% in infectious diseases. The majority of respondents felt BL TDM was relevant to their practice and improved medication effectiveness and safety (Figure 1). Two implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation which was positively influenced by repeated exposure to evidence and expertise. The process of internalization seemed more complex with BL TDM than with other antibiotics (i.e., vancomycin). Organizational considerations relevant to BL TDM implementation included adequate physical and informational infrastructure, access to trained personnel, supportive governance/leadership, and robust process and workflow development. Conclusion We found broad enthusiasm about the relevance and potential benefits of BL TDM among stakeholders. Prior literature suggested the primary barrier to implementation was assay availability, but we identified many more individual and organizational attributes which impacted the scale and spread of BL TDM. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: 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.

Background Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the first safety and pharmacokinetic data following oral administration as the isobutyryloxymethyl prodrug in humans. Methods Forty-eight healthy subjects were enrolled into one of 6 cohorts of 8 subjects each in the single ascending doses (100, 200, 400, 600, 800, and 1000 mg). Subjects were randomly assigned with each cohort to XERU oral prodrug (n = 6), or placebo capsule (n = 2). Intensive plasma (total drug) and ultrafiltrate (free drug) sampling was obtained after dosing and assayed for QPX7831 and XERU content using validated HPLC/MS methods. Results XERU PK parameters following oral administration as the prodrug are shown in the table below. Compared to IV XERU doses (data not shown), XERU bioavailability is 90 - 100% orally bioavailable. No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild in severity. Conclusion Orally administered XERU was safe and well tolerated at all doses tested. Plasma XERU AUC and Cmax increased with increasing dose. XERU exposures (24h free AUC) exceed the predicted PK-PD parameter for stasis with once-daily doses of 400 mg or higher and exceed the PK-PD parameter for 1-log of bacterial killing once daily doses of 800 mg or higher. XERU, administered as an oral prodrug, has plasma PK properties that support once-daily administration. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.

Background Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the safety and pharmacokinetics of XERU following multiple doses alone and in combination with meropenem. Methods Twenty-four healthy subjects were enrolled into one of 3 cohorts with XERU alone. XERU was administered as a 500 mg loading dose followed by 250 mg q8h or 1000 mg loading dose followed by 500 mg q8h. 15 healthy subjects were enrolled in a single cohort of meropenem alone administered as a 4000 mg loading dose followed by 2000 mg q8h or meropenem in combination with XERU administered as a 500 mg loading dose followed by 250 mg q8h for 10 days. Intensive plasma sampling was obtained after dosing and assayed for drug content using validated LC-MS/MS methods. Results XERU and Meropenem Steady State pharmacokinetic parameters are shown in the table below. No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild or moderate in severity. Conclusion XERU was safe and well-tolerated when administered alone and in combination with meropenem. XERU has unique PK properties that includes a long elimination half-life that provides sustained plasma concentrations. The loading dose of XERU allows for rapid achievement of steady state plasma levels of XERU within the first day of treatment. XERU plasma PK properties, along with a broad spectrum of inhibitory activity, facilitates its use with multiple beta-lactam antibiotics including meropenem. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Shawnee Gehrke, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.

Catheter-based methods for multichannel intraluminal impedance-pH monitoring are invasive and uncomfortable. The current alternative is a wireless system that clips to the esophageal mucosa, but which only measures pH. A shorter two-site wireless sensor that detects impedance and pH, and can be clipped to the esophagus, would be desirable. This study compares sensor positions and separations to determine the optimal configuration of a two-site wireless sensor. Records of 20 patients (10 on and 10 off proton pump inhibitor) who had ambulatory reflux testing with a multichannel intraluminal impedance-pH system (Sandhill Scientific Inc., Highlands Ranch, CO, USA) with six impedance and two pH sensors were reviewed. An investigator was blinded to four combinations of impedance channels plus pH. He read a 3-hour postprandial section from each of the combinations (total of 80 studies) and marked reflux episodes. Results were compared with his own interpretation of the full tracing. Two hundred and two total reflux episodes were analyzed, 113 acid (pH 4). Mean and median numbers of total reflux episodes were calculated. In the full study, the interpreter detected a mean of 10 reflux episodes per study. In the 5 cm and 7 cm, 3 cm and 7 cm, and 3 cm and 5 cm studies, the interpreter found a mean of 8.1, 11.1, and 9.8 reflux episodes per study, respectively. One-way analysis of variance yielded a P-value of 0.43. The trend of these preliminary findings suggests that the 3 cm and 5 cm site is the most sensitive and the 5 cm and 7 cm is the least, with the 3 cm and 7 cm site perhaps as the preferred location. The lack of a significant difference, at the very least, suggests that any of the 'mini' locations could be used. The small number of observations could have resulted in a Type II statistical error.

Extraesophageal (EE) symptoms such as cough and throat clearing are common in patients referred for reflux testing, but are less commonly associated with gastroesophageal reflux disease (GERD). Patients with reflux associated EE symptoms often lack typical GERD symptoms of heartburn and regurgitation. Our aim was to compare the frequency of proximal esophageal reflux between esophageal (typical) symptoms and EE (atypical) symptoms. Combined multichannel intraluminal impedance-pH (MII-pH) tracings were blinded by an investigator so that symptom markers were relabeled with a number without disclosure of symptom type. We selected 40 patients with at least five reflux-related symptom events for one of four symptoms (heartburn, regurgitation, cough, or throat clearing). A blinded investigator analyzed all 200 reflux episodes, reporting the proximal esophageal extent of the reflux for all symptoms. The percentage of symptom-related reflux extending proximally to 17 cm above the LES was similar among all four symptom types. At least 50% of all symptoms were associated with proximal esophageal reflux to 17 cm, with regurgitation having the highest frequency at 60%. Our data indicate that EE symptoms are not more frequently associated with proximal esophageal reflux than typical esophageal symptoms.