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Background Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. Methods Patients with infection supported on ECMO received 4–6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC–MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of f AUC0–24/MIC ≥ 8 for relebactam, and ≥40% f T > MIC for imipenem for each approved dosing regimen. Results Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ± standard deviation parameters were: CL0, 15.21 ± 6.52 L/h; Vc, 10.13 ± 2.26 L; K12, 2.45 ± 1.16 h−1 and K21, 1.76 ± 0.49 h−1 for imipenem, and 6.95 ± 1.34 L/h, 9.81 ± 2.69 L, 2.43 ± 1.13 h−1 and 1.52 ± 0.67 h−1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. Conclusions Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa. [ABSTRACT FROM AUTHOR]

Background Two of the three recently approved β-lactam agent (BL)/β-lactamase inhibitor (BLI) combinations have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam's lack of OXA-48 inhibitory activity. Methods OXA-48-positive (n  = 51) and OXA-48-negative (KPC, n  = 5; Klebsiella pneumoniae wild-type, n  = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls. Results On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a 'susceptible' MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1-log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs, and 96% (49/51) of isolates exceeded the ≥1-log bacterial reduction threshold. Conclusions Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates. [ABSTRACT FROM AUTHOR]

Background: Two out of the three recently approved β-lactam (BL)/β-lactamase inhibitors (BLIs) have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam's lack of OXA-48 inhibitory activity.Methods: OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae WT, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls.Results: On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a 'susceptible' MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1 log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs and 73% (37/51) of isolates exceeded the ≥1 log bacterial reduction threshold.Conclusions: Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates. [ABSTRACT FROM AUTHOR]

Patients hospitalized with coronavirus disease 2019 (COVID-19) often receive empiric antibiotic coverage. Procalcitonin (PCT) is a biomarker with Food and Drug Administration–approved guidance cutoffs for antibiotic use in lower respiratory tract infections. Herein we describe the implementation and impact of a pharmacist-managed PCT monitoring program in hospitalized patients with COVID-19. In this quasi-experimental, single-center, retrospective study of a prospective antimicrobial stewardship pharmacist-managed program, inpatients who were severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction positive were reviewed during weekday working hours and evaluated for appropriateness of antibiotic treatment by utilizing the PCT biomarker. As needed, the infectious diseases pharmacist offered feedback around antibiotic discontinuation in patients with PCT values ≤0.25 ng/mL. Adherence to PCT cutoffs, clinical outcomes, and utilization of health care resources were quantified and compared with a time frame immediately preceding the program's implementation. A total of 772 patients hospitalized with COVID-19 were analyzed. The pre-intervention cohort was comprised of 519 patients, and 253 patients were included after program implementation. Antibiotics were prescribed within 72 hours of admission to 232 (44.7%) and 108 (42.7%) patients during the control and intervention phases, respectively. There was no difference in the primary outcome of percentage of patients who received >1 day of antibiotic therapy (23.5% vs 21.7%; P  = .849) or in any secondary outcome including hospital length of stay, 30-day readmission rates, or discharge disposition. In a hospital where the majority of COVID-19 patients did not receive empiric antibiotics, the implementation of a pharmacist-managed PCT monitoring program did not significantly decrease antibiotic use or health care resource utilization. [ABSTRACT FROM AUTHOR]

Objectives: Previous investigations into metallo-β-lactamase (MBL)-harbouring Enterobacterales suggest that susceptibility testing in zinc-limited media may be more appropriate in predicting β-lactam in vivo activity. There are limited data with MBL-harbouring Pseudomonas aeruginosa.Methods: Forty-three MBL-harbouring P. aeruginosa isolates (IMP, n = 11; VIM, n = 12; NDM, n = 10; SPM, n = 10) and two P. aeruginosa control isolates (KPC, n = 1; WT, n = 1) were evaluated. Meropenem activity was evaluated in the murine neutropenic thigh model using humanized exposures. Susceptibility testing was conducted in conventional CAMHB, EDTA-supplemented CAMHB (3-300 mg/L EDTA) and Chelex-treated CAMHB (0-1.0 mg/L re-supplemented zinc), resulting in a range of meropenem MIC values for each isolate. A sigmoidal Emax model was fitted to fT>MIC versus change in log10 cfu/thigh to estimate the goodness of fit (R2).Results: Increasing EDTA concentrations or limiting the amount of zinc in broth resulted in several-fold reductions in MIC among the majority of the MBL-harbouring P. aeruginosa while the MICs for the KPC and WT isolates were unchanged. Bacterial killing in vivo was variable, with the range of killing spanning -3.29 to +4.81 log10 change in cfu/thigh. Addition of 30 mg/L EDTA and Chelex-treated CAMHB (with no zinc supplementation) provided broth conditions for susceptibility testing that best predicted in vivo efficacy (R2 > 0.7).Conclusions: Among MBL-harbouring P. aeruginosa, meropenem in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in EDTA-supplemented or zinc-limited broth. In addition to previous data with Enterobacterales, antibiotic susceptibility testing in media that approximates physiological conditions makes it possible to uncover potential and existing therapeutic agents. [ABSTRACT FROM AUTHOR]

• Cefepime PK in 6 critically ill patients supported by ECMO is described • In normal or augmented renal function, 2g q8h (3h infusion) achieves ≥70% f T>MIC up to 16 µg/mL • None of the patients experienced cefepime associated neurotoxicity at this dosage • TDM may be useful to balance therapeutic exposure while preventing toxicity This study determined the pharmacokinetics of cefepime in patients requiring extracorporeal membrane oxygenation (ECMO) support to guide dosage selection. Cefepime population pharmacokinetics where characterized in Pmetrics for R for six critically ill patients receiving ECMO. Simulation was employed to determine the f T>MIC and total trough concentration of varying regimens in each patient to evaluate ability to achieve optimal pharmacodynamic exposure and thresholds for cefepime-associated neurotoxicity. Of the six participants, two required continuous veno-venous hemodiafiltration (CVVHDF) while four had a CrCL between 92-199 ml/min. All patients received 2 g q8h as a 3h infusion. A two-compartment model fitted the data best with median (range) parameter estimates as follows: clearance, 5.99 (4.10-10.29) L/h; volume of central compartment, 10.08 (2.45-15.14) L; and intercompartment transfer constants (k 12), 3.58 (2.01-4.99) h-1 and k 21 , 1.70 (1.00-2.88) h-1. The 2g q8h (3h infusion) regimen resulted in >70% f T>MIC in all patients up to an MIC of 16 µg/mL, whereas 2g q12h (0.5h) resulted in 5/6 patients achieving 70% ƒT>MIC at 8 µg/mL but only 1/6 at 16 µg/mL. Aggressive dosing regimens resulted in trough concentrations exceeding conservative neurotoxicity thresholds. No patient demonstrated signs or symptoms of neurotoxicity during treatment. For ECMO patients with normal to augmented renal clearance similar to those presented here, or those receiving CVVHDF, these data support dosing regimens of 2g q8h (3h infusions) to empirically target MICs up to 16 µg/mL. Larger studies are needed to determine how ECMO affects cefepime pharmacokinetics. [ABSTRACT FROM AUTHOR]

Background: Ampicillin-sulbactam is a piperacillin-tazobactam-sparing alternative antibiotic administered as surgical prophylaxis during orthotopic liver transplant (OLT), but limited data are available describing its pharmacokinetics and impact of blood product resuscitation. The purpose of this study was to determine the intra-operative pharmacokinetics of ampicillin-sulbactam in patients during OLT and evaluate the effects of blood resuscitation on exposure. Patients and Methods: This was a pharmacokinetic study in 10 OLT patients receiving ampicillin-sulbactam surgical prophylaxis. A 5,000-patient Monte Carlo simulation was conducted to identify optimal ampicillin-sulbactam regimens. Linear regression assessed association between blood product administration and ampicillin exposures. Results: Ampicillin and sulbactam concentrations best fitted two-compartment models. Mean ampicillin pharmacokinetic parameters were central compartment volume (Vc): 6.9 ± 2.0 L, clearance (CL): 26.6 ± 18.4 L/h, and inter-compartmental rate constants (k12 and k21): 4.8 ± 2.6 and 2.3 ± 1.4 h-1. Sulbactam pharmacokinetic parameters were Vc: 8.1 ± 2.7 L, CL: 26.1 ± 7.4 L/h, k12 and k21: 4.9 ± 1.0 and 2.8 ± 1.1 h-1. Participants received between 500 and 23,642 mL of total blood product. No statistical relations were observed between blood product administration and exposures (R2 0.00-0.26). Ampicillin-sulbactam 2/1 g every two hours and 2/1 g bolus followed by 6/3 g continuous infusion provided acceptable probability of target attainment up to minimum inhibitory concentrations (MICs) of 16 and 32 mcg/mL, respectively. Conclusions: High and frequent ampicillin-sulbactam doses are required to maintain 100% fT > MIC at relevant MICs during OLT and no impact of blood product resuscitation was observed on ampicillin exposure. These are the first data available to guide ampicillin-sulbactam dosing in patients undergoing OLT. [ABSTRACT FROM AUTHOR]