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Background Cefiderocol is the first antibiotic with effluent flow rate–based dosing recommendations outlined in the product label for patients receiving continuous renal replacement therapy (CRRT). We aimed to investigate the population pharmacokinetics of cefiderocol among patients receiving CRRT and validate these dosing recommendations. Methods A multicenter, prospective cefiderocol pharmacokinetic study among intensive care unit patients receiving CRRT was conducted (2022–2023). Blood sampling was performed at steady-state and cefiderocol concentrations were assayed by validated liquid chromatography–tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration (f T > MIC) and total daily area under the concentration time curve (AUCdaily) were calculated. Results Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k12 and k21) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours−1, and 2.2 ± 2.2 hours−1, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% f T > MIC up to MIC 8 mg/L with an AUCdaily (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients. Conclusions The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUCdaily was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile. [ABSTRACT FROM AUTHOR]

Background Sulbactam dosing for Acinetobacter baumannii infections has not been standardized due to limited available pharmacokinetics/pharmacodynamics (PK/PD) data. Herein, we report a comprehensive PK/PD analysis of ampicillin-sulbactam against A. baumannii pneumonia. Methods Twenty-one A. baumannii clinical isolates were tested in the neutropenic murine pneumonia model. For dose-ranging studies, groups of mice were administered escalating doses of ampicillin-sulbactam. Changes in log10cfu/lungs relative to 0 h were assessed. Dose-fractionation studies were performed. Estimates of the percentage of of time during which the unbound plasma sulbactam concentrations exceeded the MIC (% f T > MIC) required for different efficacy endpoints were calculated. The probabilities of target attainment (PTA) for the 1-log kill plasma targets were estimated following clinically utilized sulbactam regimens. Results Dose-fractionation studies demonstrated time-dependent kill. Isolates resistant to both sulbactam and meropenem required three times the exposures to achieve 1-log kill; median [IQR] % f T > MIC of 60.37% [51.6–66.8] compared with other phenotypes (21.17 [16.0–32.9] % f T > MIC). Sulbactam standard dose (1 g q6h, 0.5 h infusion) provided >90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h, 4 h inf provided greater PTA for isolates with sulbactam-intermediate susceptibility (8 mg/L, 100% versus 86% following the standard dose). Despite the higher exposure following 3 g q8h, 4 h inf, PTA was ≤57% among sulbactam-resistant/meropenem-resistant isolates. Conclusion Sulbactam standard dose is a valuable regimen across sulbactam-susceptible isolates while the high-dose extended-infusion provides additional benefit against sulbactam-intermediate isolates. Given that most of the sulbactam-resistant A. baumannii isolates are meropenem-resistant, high-dose prolonged-infusion regimens are not expected to be effective as monotherapy against infections due to these isolates. [ABSTRACT FROM AUTHOR]

Antibiotic resistance has become a global threat as it is continuously growing due to the evolution of β‐lactamases diminishing the activity of classic β‐lactam (BL) antibiotics. Recent antibiotic discovery and development efforts have led to the availability of β‐lactamase inhibitors (BLIs) with activity against extended‐spectrum β‐lactamases as well as Klebsiella pneumoniae carbapenemase (KPC)‐producing carbapenem‐resistant organisms (CRO). Nevertheless, there is still a lack of drugs that target metallo‐β‐lactamases (MBL), which hydrolyze carbapenems efficiently, and oxacillinases (OXA) often present in carbapenem‐resistant Acinetobacter baumannii. This review aims to provide a snapshot of microbiology, pharmacology, and clinical data for currently available BL/BLI treatment options as well as agents in late stage development for CRO harboring various β‐lactamases including MBL and OXA‐enzymes. [ABSTRACT FROM AUTHOR]

Gram-negative antibiotic resistance continues to grow as a global problem due to the evolution and spread of β-lactamases. The early β-lactamase inhibitors (BLIs) are characterized by spectra limited to class A β-lactamases and ineffective against carbapenemases and most extended spectrum β-lactamases. In order to address this therapeutic need, newer BLIs were developed with the goal of treating carbapenemase producing, carbapenem resistant organisms (CRO), specifically targeting the Klebsiella pneumoniae carbapenemase (KPC). These BL/BLI combination drugs, avibactam/avibactam, meropenem/vaborbactam, and imipenem/relebactam, have proven to be indispensable tools in this effort. However, non-KPC mechanisms of resistance are rising in prevalence and increasingly challenging to treat. It is critical for clinicians to understand the unique spectra of these BL/BLIs with respect to non-KPC CRO. In Part 1of this 2-part series, we describe the non-KPC attributes of the newer BL/BLIs with a focus on utility against Enterobacterales and Pseudomonas aeruginosa. [ABSTRACT FROM AUTHOR]

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]

Intravenous β‐lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. β‐lactams are well established to display time‐dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PI) can be applied during the administration of intravenous β‐lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of β‐lactam PI developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug monitoring considerations, and the use of PI β‐lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of β‐lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP). [ABSTRACT FROM AUTHOR]

Background: A Best Practice Advisory (BPA) warns clinicians of an interaction between carbapenems and valproic acid (VPA) that can cause significant declines in VPA levels leading to serious consequences for patients treated for seizure disorder and unknown implications for alternative indications. Objective: The goal of this study was to assess BPA efficacy in avoiding concomitant VPA/carbapenems, and to characterize use of these agents, clinical implications, and potential alternative therapeutic options. Methods: Retrospective chart review was performed on all patients over the course of 1 year who were concomitantly prescribed a carbapenem and VPA at Hartford Hospital, Hartford, CT. Data collected included: level of care, duration of concomitant therapy, indications, VPA levels during or surrounding overlap, documentation of the interaction, and therapeutic implications. Results: Carbapenems and VPA were administered to 591 and 625 patients, respectively; the BPA fired 126 times in 24 patients, and 15 patients were initiated on these agents concomitantly. Eight (53%) patients received VPA for seizures. The remaining seven (47%) received VPA for alternative indications. Eight of nine VPA levels were sub-therapeutic during carbapenem therapy and polypharmacy was administered in all patients receiving VPA for non-convulsive indications. Conclusion: Co-prescribing of these drugs was rare; however, the BPA was ineffective in 63% of instances. Reductions in VPA efficacy for any indication should be expected with concomitant carbapenem administration. Antibiotics other than carbapenems should be considered when coverage of multidrug resistant Gram-negative pathogens is required in patients whose VPA treatment cannot be interrupted or switched to a therapeutic alternative. [ABSTRACT FROM AUTHOR]

Purpose: Following updates to the Infectious Diseases Society of America (IDSA) practice guidelines for the Diagnosis and Treatment of Adults with Community-acquired Pneumonia in 2019, Hartford HealthCare implemented changes to the community acquired pneumonia (CAP) order-set in August 2020 to reflect criteria for the prescribing of broad-spectrum antimicrobial therapy. The objective of the study was to evaluate changes in broad-spectrum antibiotic days of therapy (DOT) following these order-set updates with accompanying provider education. Methods: This was a multi-center, quasi-experimental, retrospective study of patients with a diagnosis of CAP from September 1, 2019 to October 31, 2019 (pre-intervention) and September 1, 2020 to October 31, 2020 (post-intervention). Patients were identified using ICD-10 codes (A48.1, J10.00-J18.9) indicating lower respiratory tract infection. Data collected included demographics, labs and vitals, radiographic, microbiological, and antibiotic data. The primary outcome was change in broad-spectrum antibiotic DOT, specifically anti-pseudomonal β-lactams and anti-MRSA antibiotics. Secondary outcomes included guideline-concordance of initial antibiotics, utilization of an order-set to prescribe antibiotics, and length of stay (LOS). Results: A total of 331 and 352 patients were included in the pre- and post-intervention cohorts, respectively. There were no differences in order-set usage (10% vs 11.3%, P =.642) between the pre- and post-intervention cohort, respectively. The overall duration of broad-spectrum therapy was a median of 2 days (IQR 0-8 days) in the pre-intervention period and 0 days (IQR 0-4 days) in the post-intervention period (P <.001). Patients in whom the order-set was used in the post-intervention period were more likely to have guideline-concordant regimens ([36/40] 90% vs [190/312] 60.9%; P =.003). Hospital LOS was shorter in the post-intervention cohort (4.8 days [2.9-7.2 days] vs 5.3 days [IQR 3.5-8.5 days], P =.002). Conclusion: Implementation of an updated CAP order-set with accompanying provider education was associated with reduced use of broad-spectrum antibiotics. Opportunities to improve compliance and thus further increase guideline-concordant therapy require investigation. [ABSTRACT FROM AUTHOR]

Background: Levofloxacin displays in vitro activity against Stenotrophomonas maltophilia (STM); however, current susceptibility breakpoints are supported by limited data. We employed the murine neutropenic thigh infection model to assess levofloxacin pharmacodynamics against STM.Methods: Twenty-six clinical STM were studied using the neutropenic murine thigh infection model. Human simulated regimens (HSR) of levofloxacin 750 mg q24h were administered over 24 h. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h. Composite cfu data were fitted to an Emax model to determine the fAUC/MIC needed for stasis and 1 log10 reduction at 24 h. Monte Carlo simulation was performed to determine PTA.Results: Levofloxacin MICs ranged from 0.5-8 mg/L. Mean bacterial burden at 0 h was 6.21 ± 0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 ± 0.66 log10 cfu/thigh. In isolates with levofloxacin MICs ≤1, 2 and ≥4 mg/L, changes in bacterial density following levofloxacin HSR were -1.66 ± 0.89, 0.13 ± 0.97 and 1.54 ± 0.43 log10 cfu/thigh, respectively. The Emax model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log10 reduction threshold were 95.8, 72.2, and 26.6% at MICs of 0.5, 1 and 2 mg/L, respectively.Conclusions: These are the first data to describe fAUC/MIC thresholds predictive of cfu reductions for levofloxacin against STM. Due to poor in vivo efficacy and PTA at MICs ≥2 mg/L, reassessment of the current susceptibility breakpoint is warranted. [ABSTRACT FROM AUTHOR]

Purpose Sulbactam/durlobactam is a combination antibiotic designed to target Acinetobacter baumannii , including carbapenem-resistant and multidrug-resistant strains. The objective of this study was to determine the physical compatibility of sulbactam/durlobactam solution during simulated Y-site administration with 95 intravenous (IV) drugs. Methods Vials of sulbactam/durlobactam solution were diluted in 0.9% sodium chloride injection to a volume of 100 mL (the final concentration of both drugs was 15 mg/mL). All other IV drugs were reconstituted according to the manufacturer's recommendations and diluted with 0.9% sodium chloride injection to the upper range of concentrations used clinically or tested undiluted as intended for administration. Y-site conditions were simulated by mixing 5 mL of sulbactam/durlobactam with 5 mL of the tested drug solutions in a 1:1 ratio. Solutions were inspected for physical characteristics (clarity, color, and Tyndall effect), turbidity, and pH changes before admixture, immediately post admixture, and over 4 hours. Incompatibility was defined as any observed precipitation, significant color change, positive Tyndall test, or turbidity change of ≥0.5 nephelometric turbidity unit during the observation period. Results Sulbactam/durlobactam was physically compatible with 38 out of 42 antimicrobials tested (90.5%) and compatible overall with 86 of 95 drugs tested (90.5%). Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, ciprofloxacin, daptomycin, levofloxacin, phenytoin sodium, vecuronium, and propofol. Conclusion The Y-site compatibility of sulbactam/durlobactam with 95 IV drugs was described. These compatibility data will assist pharmacists and nurses to safely coordinate administration of IV medications with sulbactam/durlobactam. [ABSTRACT FROM AUTHOR]

Empiric antibiotics may affect bacterial pathogen recovery using conventional culture methods (CCMs), while PCR-based diagnostics are likely less affected. Herein, we conducted an in vitro study of bronchoalveolar lavage fluid (BAL) inoculated with bacteria and clinically relevant antibiotic concentrations to compare the recovery between the BioFire FILMARRAY Pneumonia Panel (Pn Panel) and CCMs. Remnant clinical BAL specimens were inoculated to ~10 5 cfu/mL using 12 clinical isolates. Isolates consisted of one wild-type (WT) and one or more resistant strains of: Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Acinetobacter baumannii , and Staphylococcus aureus . Piperacillin-tazobactam, cefepime, meropenem, levofloxacin, or vancomycin was added to achieve pulmonary epithelial lining fluid peak and trough concentrations. Post-exposure cfu/mL was quantified by CCMs and simultaneously tested by the PN Panel for identification and semi-quantitative genetic copies/mL. CCM results were categorized as significant growth (SG) (≥1 × 10 4 ), no significant growth (NSG) (≥1 × 10 3 , <1 × 10 4 ), or no growth (NG) (<1 × 10 3 ). The PN Panel accurately identified all isolates, resistance genes, and reported ≥10 6 genetic copies/mL regardless of antibiotic exposure. The CCM also identified all S. aureus strains exposed to vancomycin. For WT Gram-negative isolates exposed to antibiotics, SG, NSG, and NG were observed in 7/52 (13%), 18/52 (35%), and 27/52 (52%) of CCM experiments, respectively. For resistant Gram-negatives isolates, SG, NSG, and NG were observed in 62/88 (70%), 17/88 (19%), and 9/88 (10%), respectively. These in vitro data demonstrate that the PN Panel is able to identify Gram-negative pathogens in the presence of clinically significant antibiotic concentrations when CCM may not., Competing Interests: The authors declare no conflict of interest.

Pseudomonas aeruginosa is a common multidrug-resistant pathogen in patients with cystic fibrosis (CF). The in vitro activity of imipenem/relebactam and imipenem was compared with other antipseudomonal antibiotics against 105 isolates from patients with CF from three US hospitals. Imipenem/relebactam, imipenem, meropenem, ceftazidime/avibactam, and ceftolozane/tazobactam susceptibilities were 77%, 55%, 58%, 90%, and 92%, respectively. Relebactam potentiates imipenem against CF P. aeruginosa by fourfold leading imipenem/relebactam to retain susceptibility against most isolates in this cohort., Competing Interests: D.P.N. and J.L.K. have received research funding from Merck and Co, Inc. The other authors have no conflict of interest to disclose.

Background: Levofloxacin displays in vitro activity against Stenotrophomonas maltophilia (STM); however, current susceptibility breakpoints are supported by limited data. We employed the murine neutropenic thigh infection model to assess levofloxacin pharmacodynamics against STM., Methods: Twenty-six clinical STM were studied using the neutropenic murine thigh infection model. Human simulated regimens (HSR) of levofloxacin 750 mg q24h were administered over 24 h. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h. Composite cfu data were fitted to an Emax model to determine the fAUC/MIC needed for stasis and 1 log10 reduction at 24 h. Monte Carlo simulation was performed to determine PTA., Results: Levofloxacin MICs ranged from 0.5-8 mg/L. Mean bacterial burden at 0 h was 6.21 ± 0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 ± 0.66 log10 cfu/thigh. In isolates with levofloxacin MICs ≤1, 2 and ≥4 mg/L, changes in bacterial density following levofloxacin HSR were -1.66 ± 0.89, 0.13 ± 0.97 and 1.54 ± 0.43 log10 cfu/thigh, respectively. The Emax model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log10 reduction threshold were 95.8, 72.2, and 26.6% at MICs of 0.5, 1 and 2 mg/L, respectively., Conclusions: These are the first data to describe fAUC/MIC thresholds predictive of cfu reductions for levofloxacin against STM. Due to poor in vivo efficacy and PTA at MICs ≥2 mg/L, reassessment of the current susceptibility breakpoint is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)