In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral β-lactam/β-lactamase inhibitor combination.

Objectives: Oral β-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable β-lactamase inhibitor that restores ceftibuten activity against Ambler Class A-, C- and D-producing Enterobacterales. We assessed the ledaborbactam exposure needed to produce bacteriostasis against ceftibuten-resistant Enterobacterales in the presence of humanized ceftibuten exposures in the neutropenic murine thigh infection model.

Evaluation of the in vitro activity of WCK 5222 (cefepime/zidebactam) and currently available combination therapies against single- and double-carbapenemase producing Enterobacteriaceae: Expanding the zone of hope.

Cefepime/zidebactam (WCK 5222) is a β-lactam/β-lactam enhancer antibiotic designed to retain in vitro activity against Enterobacteriaceae that simultaneously produce metallo-β-lactamase (MBL) and serine-β-lactamase (SBL). Aztreonam (ATM) plus ceftazidime/avibactam (CZA) or meropenem/vaborbactam (M/V) is an attractive option for coverage of such strains, but clinical laboratories are not equipped to distinguish which is the more potent regimen to inform treatment decisions. We evaluated Enterobacteriaceae that expressed MBL and ≥1 SBL (n=15) using gradient diffusion strip (GDS) methods to (1) determine the minimum inhibitory concentration (MIC) of WCK 5222 and (2) compare the in vitro potency of CZA+ATM vs.

Comparative Evaluation of the Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant .

The activity of WCK 5222 (cefepime-zidebactam) was compared to that of several available combination therapies among 30 clinical carbapenem-resistant (CRP) strains using gradient diffusion strips. The combinations included nonsusceptible β-lactams (cefepime, ceftolozane-tazobactam, and meropenem) with amikacin and fosfomycin. WCK 5222 MICs ranged from 2 to 32 mg/liter, and 97% were ≤16 mg/liter, while 105/146 (72%) combinations demonstrated inhibition below established susceptibility breakpoints.

Assessment of the Physical Compatibility of Eravacycline and Common Parenteral Drugs During Simulated Y-site Administration.

Purpose: Eravacycline is a broad-spectrum, intravenous fluorocycline antibiotic approved for the treatment of complicated intra-abdominal infections in adults. A 60-minute infusion is recommended for each infused dose. Compatibility data that may allow convenient Y-site administration of eravacycline with other parenteral medications are unavailable.

Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia.

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteraemia. Whilst a free drug area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) ratio >27.4 is associated with 30-day survival with daptomycin monotherapy, it is unknown whether receipt of other antibiotics affects this threshold.

In vitro investigation of synergy among fosfomycin and parenteral antimicrobials against carbapenemase-producing Enterobacteriaceae.

Intravenous fosfomycin is undergoing clinical development in the United States for treatment of complicated urinary tract infections (cUTIs) and may be prescribed as a component of dual antibiotic regimens against carbapenemase-producing Enterobacteriaceae (CPE). Fosfomycin, aztreonam, cefepime, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, piperacillin/tazobactam, and tobramycin minimum inhibitory concentrations (MICs) were determined by gradient diffusion strip (GDS) against CPE isolates (N = 49). The GDS cross method was used to assess antibiotic interactions between fosfomycin and the aforementioned parenteral antibiotics.

Prevalence of in vitro synergistic antibiotic interaction between fosfomycin and nonsusceptible antimicrobials in carbapenem-resistant Pseudomonas aeruginosa.

Purpose: We assessed the synergistic potential of fosfomycin and parenteral antibiotics among carbapenem-resistant Pseudomonas aeruginosa (CRP).

Methodology: Minimum inhibitory concentrations (MICs) were determined by broth microdilution for all antibiotics except fosfomycin, for which the gradient diffusion strip (GDS) method was used. The GDS cross method was performed to assess interactions between fosfomycin and: aztreonam, cefepime, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, piperacillin/tazobactam and tobramycin.

Where should antibiotic gradient diffusion strips be crossed to assess synergy? A comparison of the standard method with a novel method using steady-state antimicrobial concentrations.

Multi-drug resistance among Pseudomonas aeruginosa in hospitals, and particularly intensive care units, has achieved alarming rates. Some combination antimicrobial therapies have demonstrated promising synergistic effects and an ability to overcome resistance without increasing drug-related toxicities. Nevertheless, rapid and feasible methods to identify synergy have not been routinely implemented in clinical microbiology laboratories.

Impact of a co-curricular, e-learning activity on pharmacy student knowledge of laboratory values.

Background And Purpose: Pharmacists are increasingly taking on roles that require interpretation of laboratory values. We sought to assess the impact of a co-curricular, e-learning activity on pharmacy student knowledge of laboratory values.

Educational Activity And Setting: We implemented a co-curricular, e-learning activity during the 2015-2016 academic year at the South Carolina College of Pharmacy.

Efficacy of Humanized WCK 5222 (Cefepime-Zidebactam) Exposures against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Thigh Model.

Herein, we describe the efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against carbapenem-resistant strains in a neutropenic murine thigh infection model. Five of the six isolates examined expressed OXA-23 or OXA-24. WCK 5222, despite showing MICs of 16 to 64 mg/liter, produced remarkable activity; human-simulated exposure showed a decline in the bacterial burden for all isolates (mean reduction, -2.

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

Background: Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined.

Assessment of the Efficacy of WCK 5222 (Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model.

We evaluated the efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant strains ( = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. In control animals and those that received cefepime or zidebactam alone, the mean bacterial growth at 24 h was >2 log CFU/lung compared with 0-h controls (6.

Assessing the in vitro activity of ceftazidime/avibactam and aztreonam among carbapenemase-producing Enterobacteriaceae: Defining the zone of hope.

Ceftazidime/avibactam plus aztreonam (CZA+ATM) is an emerging option to combat carbapenemase-producing Enterobacteriaceae (CPE) expressing resistance via multiple β-lactamases within Ambler classes A, B, C, and D. The benefit of this combination is apparent when the pathogen-specific resistance genotype is characterized. However, rapid molecular diagnostic systems may be unavailable to allow this precision medicine-based approach.

Physical compatibility of plazomicin with select i.v. drugs during simulated Y-site administration.

Purpose: The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported.

Characterization of Potentially Unsafe Ambulatory Antibiotic Use and Associated Outcomes in an Adult Kidney Transplant Population.

Background: Antibiotics are frequently prescribed to kidney transplant (KTX) recipients in the outpatient setting, but there are limited data assessing the safety and outcomes associated with this practice.

Objective: The primary objective of this study was to describe ambulatory antibiotic prescribing in a large cohort of adult KTX recipients. The secondary objective was to assess the outcomes associated with potentially unsafe antibiotic use in this population.

Investigational drugs for the treatment of infections caused by multidrug-resistant Gram-negative bacteria.

Introduction: Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii.

Areas Covered: The authors summarize in vitro and in vivo efficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB.

Physical Compatibility of Meropenem and Vaborbactam With Select Intravenous Drugs During Simulated Y-site Administration.

Purpose: Meropenem/vaborbactam is a novel intravenous antibiotic combining the carbapenem, meropenem, with a novel β-lactamase inhibitor, vaborbactam. Meropenem/vaborbactam is administered as a 3-hour infusion given every 8 hours, thereby potentially restricting an intravenous line for 9 h/d. Intravenous medications may be given concurrently via Y-site when compatibility data are available.

Bipolar depression: Managing patients with second generation antipsychotics.

Bipolar affective disorder is a debilitating illness that manifests as cyclical episodes of mood elevation and depression, but the treatment of the depressive episodes (i.e., bipolar depression) differs considerably from the treatment of major depressive disorder.