IntroductionThe scope of extracorporeal membrane oxygenation (ECMO) is expanding; however, optimal drug prescription during ECMO remains a developing science. Currently, there are no clear guidelines for antibiotic dosing during ECMO. This open-label, descriptive, matched-cohort pharmacokinetics (PK) study aimed to compare the PK of meropenem in ECMO patients to critically ill patients with sepsis not receiving ECMO (controls).MethodsEleven adult patients on ECMO (venovenous (VV) ECMO, n = 6; venoarterial (VA) ECMO, n = 5) receiving intravenous (IV) meropenem were included. Meropenem plasma concentrations were determined using validated chromatography. Population PK analysis was performed using non-linear mixed effects modelling. This data was compared with previously published meropenem PK data from 10 critically ill adult patients not on ECMO (preserved renal function (n = 5) or receiving renal replacement therapy (RRT) (n = 5). Using these data, we then performed Monte Carlo simulations (n = 1,000) to describe the effect of creatinine clearance on meropenem plasma concentrations.ResultsIn total, five (two VV, three VA) out of eleven ECMO patients received RRT. The other six patients (four VV, two VA) had no significant impairment in renal function. A two-compartment model adequately described the data. ECMO patients had numerically higher volume of distribution (0.45 ± 0.17 versus 0.41 ± 0.13 L/kg, P = 0.21) and lower clearance compared to controls (7.9 ± 5.9 versus 11.7 ± 6.5 L/h, P = 0.18). Variability in meropenem clearance was correlated with creatinine clearance or the presence of RRT. The observed median trough concentrations in the controls were 4.2 (0.0 to 5.7) mg/L. In ECMO patients, while trough meropenem concentrations >2 mg/L were achieved in all patients, a more aggressive target of >8 mg/L for less susceptible microorganisms was observed in only eight out of eleven patients, with five of them being on RRT.ConclusionsECMO patients exhibit high PK variability. Decreased meropenem CL on ECMO appears to compensate for ECMO and critical illness-related increases in volume of distribution. Routine target concentrations >2 mg/L are maintained with standard dosing (1 g IV 8-hourly). However, an increase in dose may be necessary when targeting higher concentrations or in patients with elevated creatinine clearance.

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.

ObjectiveTo evaluate the stability of temocillin solution in two elastomeric infusion devices – Easypump II LT 270–27- S and Dosi-Fusor L25915-250D1 for OPAT administration during 14 days of 5°C±3°C fridge storage followed by 24 hour exposure at an in-use temperature of 32°C, when reconstituted with 0.3% citrate buffer at pH7.MethodsStability testing was conducted in accordance with standard protocols in the UK National Health Service Yellow Cover Document (YCD). A stability indicating assay method was applied using a high-performance liquid chromatography (HPLC) system with a photodiode array detector. Low (500 mg/240 mL), intermediate (4000 mg/240 mL) and high (6000 mg/240 mL) temocillin concentrations were tested in triplicate devices with duplicate samples taken at 11 time points during fridge storage and subsequent in-use temperature exposure.ResultThe percentage of temocillin remaining after 14 days of fridge storage was greater than 97% in both devices and at all concentrations tested. During subsequent in-use temperature exposure, a 95% stability limit was achieved for 12 hours except for the high concentration (25 mg/mL) in the Dosi-Fusor device. It met this criterion for only 10 hours — the percent of temocillin remaining at 12 hours was 94.5%. However, for all devices and the doses tested, the degradation of temocillin was <9% at the end of 24 hours in-use temperature exposure.ConclusionTemocillin reconstituted with 0.3% citrate buffer at pH7 in elastomeric infusion devices can be stored in a fridge (2°C–8°C) for 14 days meeting the YCD acceptance criteria. Considering <5% degradation, the current data supports twice daily dosing of temocillin within the OPAT setting. In jurisdictions where a <10% degradation limit is acceptable, once daily dosing with 24-hour continuous infusion may be considered. Temocillin is a useful alternative to other broad-spectrum anti-Gram-negative agents currently utilised in the OPAT setting and supports the wider antimicrobial stewardship agenda.

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.