Aztreonam/avibactam effect on pharmacodynamic indices for mutant selection of Escherichia coli and Klebsiella pneumoniae harbouring serine- and New Delhi metallo-ß-lactamases.

OBJECTIVES: Ceftazidime/avibactam is not active against MBL-producing bacteria. Combining ceftazidime/avibactam or avibactam with aztreonam can counter the resistance of MBL-producing Enterobacterales. The aim of this study was to evaluate whether the addition of avibactam could reduce or close the mutant selection window (MSW) of aztreonam in Escherichia coli and Klebsiella pneumoniae harbouring MBLs; MSW is a pharmacodynamic (PD) parameter for the selection of emergent resistant mutants. METHODS: In vitro susceptibility of 19 clinical isolates to ceftazidime/avibactam, aztreonam alone, and in co-administration (aztreonam/ceftazidime/avibactam and aztreonam/avibactam) was determined, as well as the mutant prevention concentration (MPC). The fraction of time within 24 h that the free drug concentration was within the MSW (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) in both plasma and epithelial lining fluid (ELF) were determined from simulations of 10 000 profiles. The joint PTA was used to derive a joint cumulative fraction of response (CFR). RESULTS: All isolates were resistant to ceftazidime/avibactam or aztreonam. Combining aztreonam and avibactam or ceftazidime/avibactam resulted in synergistic bactericidal activities against all isolates. Synergism was primarily due to the aztreonam/avibactam combination. For aztreonam/avibactam dosing regimens evaluated in clinical trials, fT>MPC values were >90% and >80%, whereas fTMSW measures were <10% and <20% in plasma and ELF, respectively. The CFR was 100% for aztreonam/avibactam against the collection of clinical isolates. CONCLUSIONS: Effective antimicrobial combination optimized the PD parameters measuring selection for emergent mutants by increasing fT>MPC and reducing fTMSW.

A Near-Isotropic Proton-Conducting Porous Graphene Oxide Membrane.

A graphene oxide (GO) membrane is an ideal separator for multiple applications due to its morphology, selectivity, controllable oxidation, and high aspect ratio of the 2D nanosheet. However, the anisotropic ion conducting nature caused by its morphology is not favorable toward through-plane conductivity, which is vital for solid-state electrolytes in electrochemical devices. Here, we present a strategy to selectively enhance the through-plane proton conductivity of a GO membrane by reducing its degree of anisotropy with pore formation on the nanosheets through the sonication-assisted Fenton reaction. The obtained porous GO (pGO) membrane is a near-isotropic, proton-conducting GO membrane, showing a degree of anisotropy as low as 2.77 and 47% enhancement of through-plane proton conductivity as opposed to the pristine GO membrane at 25 °C and 100% relative humidity. The anisotropic behavior shows an Arrhenius relationship with temperature, while the water interlayer formation between nanosheets plays a pivotal role in the anisotropic behavior under different values of relative humidity (RH); that is, as low RH increases, water molecules tend to orient in a bimodal distribution clinching the nanosheets and forming a subnanometer, high-aspect-ratio, water interlayer, resulting in its peak anisotropy. Further increase in RH fills the interlayer gap, resulting in behaviors akin to near-isotropic, bulk water. Lastly, implementation of the pGO membrane, as the solid proton-conductive electrolyte, in an alcohol fuel cell sensor has been demonstrated, showcasing the excellent selectivity and response, exceptional linearity, and ethanol detection limits as low as 25 ppm. The amalgamation of excellent performance, high customizability, facile scalability, low cost, and environmental friendliness in the present method holds considerable potential for transforming anisotropic GO membranes into near-isotropic ion conductors to further membrane development and sensing applications.

Revealing the Rapid Electrocatalytic Behavior of Ultrafine Amorphous Defective Nb2O5-x Nanocluster toward Superior Li-S Performance.

The notorious shuttling behaviors and sluggish conversion kinetics of the intermediate lithium polysulfides (LPS) are hindering the practical application of lithium sulfur (Li-S) batteries. Herein, an ultrafine, amorphous, and oxygen-deficient niobium pentoxide nanocluster embedded in microporous carbon nanospheres (A-Nb2O5-x@MCS) was developed as a multifunctional sulfur immobilizer and promoter toward superior shuttle inhibition and conversion catalyzation of LPS. The A-Nb2O5-x nanocluster implanted framework uniformizes sulfur distribution, exposes vast active interfaces, and offers a reduced ion/electron transportation pathway for expedited redox reaction. Moreover, the low crystallinity feature of A-Nb2O5-x manipulates the LPS chemical affinity, while the defect chemistry enhances the intrinsic conductivity and catalytic activity for rapid electrochemical conversions. Attributed to these superiorities, A-Nb2O5-x@MCS delivers good Li-S battery performances, that is, high areal capacity of 6.62 mAh cm-2 under high sulfur loading and low electrolyte/sulfur ratio, superb rate capability, and cyclability over 1200 cycles with an ultralow capacity fading rate of 0.024% per cycle. This work provides a synergistic regulation on crystallinity and oxygen deficiency toward rapid and durable sulfur electrochemistry, holding a great promise in developing practically viable Li-S batteries and enlightening material engineering in related energy storage and conversion areas.

"Ship in a Bottle" Design of Highly Efficient Bifunctional Electrocatalysts for Long-Lasting Rechargeable Zn-Air Batteries.

The poor durability of bifunctional oxygen electrocatalysts is one main bottleneck that suppresses the widespread application of rechargeable metal-air batteries. Herein, a "ship in a bottle" design is achieved by impregnating fine transition metal dichalcogenide nanoparticles into defective carbon pores that act as interconnected nanoreactors. The erected 3D porous conductive architecture provides a "highway" for expediting charge and mass transfer. This design not only delivers a high surface-to-volume ratio to increase numbers of exposed catalytic sites but also precludes nanoparticles from aggregation during cycling owing to the pore spatial confinement effect. Therefore, the long-term plague inherent to nanocatalyst stability can be solved. Moreover, the synergistic coupling effects between defect-rich interfaces and chemical bonding derived from heteroatom-doping boost the catalytic activity and prohibit the detachment of nanoparticles for better stability. Consequently, the developed catalyst presents superior bifunctional oxygen electrocatalytic activities and durability, out-performing the best-known noble-metal benchmarks. In a practical application to rechargeable Zn-air batteries, long-term cyclability for over 340 h is realized at a high current density of 25 mA cm-2 in ambient air while retaining an intact structure. Such a universal "ship in a bottle" design offers an appealing and instructive model of nanomaterial engineering for implementation in various fields.

Pharmacodynamic Attainment of the Synergism of Meropenem and Fosfomycin Combination against Pseudomonas aeruginosa Producing Metallo-ß-Lactamase.

Fosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in both in vitro and clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-ß-lactamase (MBL)-producing Pseudomonas aeruginosa strains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producing P. aeruginosa strains. The MICs of both antimicrobials were determined by the checkerboard method and analyzed by two synergism tests with 19 clones of P. aeruginosa isolates, 10 of which were MBL producers. A pharmacodynamic (PD) analysis was performed for meropenem (administered at 1 g every 8 h [q8h], 1.5 g every 6 h [q6h], and 2 g q8h) and fosfomycin (administered at 4 g q8h, 4 g q6h, 6 g q8h, and 8 g q8h) regimens with a dose reduction for renal impairment by determining the probability of target attainment (PTA) for target PD indices of meropenem (the percentage of the time in a 24-h duration at which the free drug concentration remains above the MIC [fT>MIC], ≥40%) and fosfomycin (the ratio of the area under the free drug concentration-versus-time curve over 24 h and the MIC [fAUC/MIC], ≥40.8). The combination reduced the MIC50 and MIC90 by 8-fold. Seven (44%) isolates with MICs in the intermediate or resistant ranges became sensitive to meropenem. For the MBL-producing isolates, the combination resulted in 40% of isolates becoming sensitive to meropenem. The meropenem regimens reached a PTA of ≥90% (MIC = 4 µg/ml) in 6 (32%) isolates when they were used as monotherapy and 13 (68%) isolates when they were combined with fosfomycin. None of the fosfomycin monotherapy regimens reached the PTA of ≥90% (MIC = 16 µg/ml). When combined with meropenem, the fosfomycin regimens reached the PTA of ≥90% in 14 (74%) isolates. The increase in pharmacodynamic activities resulting from the synergistic action of meropenem with fosfomycin demonstrates the potential relevance of this combination to fight infections caused by MDR and MBL-producing P. aeruginosa strains.

Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime-Avibactam Combination: A Model-Informed Strategy for its Clinical Development.

Avibactam is a non-ß-lactam, ß-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its ß-lactamase targets, encompassing extended spectrum of activities that cover serine ß-lactamases but not metallo-ß-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary elimination pathway of both ceftazidime and avibactam, and dose adjustment is required in patients with moderate and severe renal impairment. Population PK models of ceftazidime and avibactam were developed separately and incorporated body weight, disease state, ethnicity, and renal function (creatinine clearance) as covariates of clearance and volume of distribution. The clinical dosing regimen of ceftazidime/avibactam combination was determined from population PK model simulations in the patient population for dosing regimens that can achieve sufficient joint probability of target attainment for ceftazidime minimum inhibitory concentration (MIC) of 8 mg/L at a fixed 4 mg/L avibactam concentration (MIC ≤ 8/4 mg/L); 8 mg/L is the breakpoint of ceftazidime in Enterobacteriaceae and Pseudomonas aeruginosa for the target pharmacodynamic indices of ceftazidime and avibactam of 50% time at which the free ceftazidime concentration is above the MIC (fT > MIC) and 50% time at which the free avibactam is above a threshold concentration of 1 mg/L (fT > CT). Whereas the static index approach does not take into account the changing potency of ceftazidime in the presence of changing avibactam concentration, a mathematical model based on kill-curve kinetics was utilized to validate the dose selection in humans. The clinical dosing regimen of 2/0.5 g ceftazidime/avibactam administered every 8 h as a 2-h intravenous infusion in patients with normal renal function, with dose adjustment in renal impairment, demonstrated statistical non-inferiority to carbapenem in phase III studies on the treatment of complicated intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia, including ceftazidime non-susceptible Gram-negative pathogens. The success of the phase III studies validated the dose selection and exposure target that were associated with efficacy based on a model-informed approach.

Molecular Functionalization of Graphene Oxide for Next-Generation Wearable Electronics.

Acquiring reliable and efficient wearable electronics requires the development of flexible electrolyte membranes (EMs) for energy storage systems with high performance and minimum dependency on the operating conditions. Herein, a freestanding graphene oxide (GO) EM is functionalized with 1-hexyl-3-methylimidazolium chloride (HMIM) molecules via both covalent and noncovalent bonds induced by esterification reactions and electrostatic πcation-π stacking, respectively. Compared to the commercial polymeric membrane, the thin HMIM/GO membrane demonstrates not only slightest performance sensitivity to the operating conditions but also a superior hydroxide conductivity of 0.064 ± 0.0021 S cm(-1) at 30% RH and room temperature, which was 3.8 times higher than that of the commercial membrane at the same conditions. To study the practical application of the HMIM/GO membranes in wearable electronics, a fully solid-state, thin, flexible zinc-air battery and supercapacitor are made exhibiting high battery performance and capacitance at low humidified and room temperature environment, respectively, favored by the bonded HMIM molecules on the surface of GO nanosheets. The results of this study disclose the strong potential of manipulating the chemical structure of GO to work as a lightweight membrane in wearable energy storage devices, possessing highly stable performance at different operating conditions, especially at low relative humidity and room temperature.