Nacubactam enhances meropenem activity against carbapenem-resistant klebsiella pneumoniae producing KPC

Carbapenem-resistant Enterobacteriaceae (CRE) are resistant to most antibiotics, making CRE infections extremely difficult to treat with available agents. Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) are predominant carbapenemases in CRE in the United States. Nacubactam is a bridged diazabicyclooctane (DBO) -lactamase inhibitor that inactivates class A and C -lactamases and exhibits intrinsic antibiotic and -lactam “enhancer” activity against Enterobacteriaceae. In this study, we examined a collection of meropenem-resistant K. pneumoniae isolates carrying blaKPC-2 or blaKPC-3; meropenem-nacubactam restored susceptibility. Upon testing isogenic Escherichia coli strains producing KPC-2 variants with single-residue substitutions at important Ambler class A positions (K73, S130, R164, E166, N170, D179, K234, E276, etc.), the K234R variant increased the meropenem-nacubactam MIC compared to that for the strain producing KPC-2, without increasing the meropenem MIC. Correspondingly, nacubactam inhibited KPC-2 (apparent Ki [Kiapp] 31 3 M) more efficiently than the K234R variant (Kiapp 270 27 M) and displayed a faster acylation rate (k2/K), which was 5,815 582 M1 s1 for KPC-2 versus 247 25 M1 s1 for the K234R variant. Unlike avibactam, timed mass spectrometry revealed an intact sulfate on nacubactam and a novel peak (337 Da) with the K234R variant. Molecular modeling of the K234R variant showed significant catalytic residue (i.e., S70, K73, and S130) rearrangements that likely interfere with nacubactam binding and acylation. Nacubactam’s aminoethoxy tail formed unproductive interactions with the K234R variant’s active site. Molecular modeling and docking observations were consistent with the results of biochemical analyses. Overall, the meropenem-nacubactam combination is effective against carbapenem-resistant K. pneumoniae. Moreover, our data suggest that -lactamase inhibition by nacubactam proceeds through an alternative mechanism compared to that for avibactam

ARGONAUT-I: Activity of cefiderocol (s-649266), a siderophore cephalosporin, against gram-negative bacteria, including carbapenem-resistant nonfermenters and enterobacteriaceae with defined extended-spectrum β-lactamases and carbapenemases

The activity of the siderophore cephalosporin cefiderocol is targeted against carbapenem-resistant Gram-negative bacteria. In this study, the activity of cefiderocol against characterized carbapenem-resistant Acinetobacter baumannii complex, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Enterobacteriaceae strains was determined by microdilution in iron-depleted Mueller-Hinton broth. The MIC90s against A. baumannii, S. maltophilia, and P. aeruginosa were 1, 0.25, and 0.5 mg/ liter, respectively. Against Enterobacteriaceae, the MIC90 was 1 mg/liter for the group harboring OXA-48-like, 2 mg/liter for the group harboring KPC-3, and 8 mg/liter for the group harboring TEM/SHV ESBL, NDM, and KPC-2

Reactive Halogens in the Marine Boundary Layer (RHaMBLe): The tropical North Atlantic experiments

The NERC UK SOLAS-funded Reactive Halogens in the Marine Boundary Layer (RHaMBLe) programme comprised three field experiments. This manuscript presents an overview of the measurements made within the two simultaneous remote experiments conducted in the tropical North Atlantic in May and June 2007. Measurements were made from two mobile and one ground-based platforms. The heavily instrumented cruise D319 on the RRS Discovery from Lisbon, Portugal to São Vicente, Cape Verde and back to Falmouth, UK was used to characterise the spatial distribution of boundary layer components likely to play a role in reactive halogen chemistry. Measurements onboard the ARSF Dornier aircraft were used to allow the observations to be interpreted in the context of their vertical distribution and to confirm the interpretation of atmospheric structure in the vicinity of the Cape Verde islands. Long-term ground-based measurements at the Cape Verde Atmospheric Observatory (CVAO) on São Vicente were supplemented by long-term measurements of reactive halogen species and characterisation of additional trace gas and aerosol species during the intensive experimental period. This paper presents a summary of the measurements made within the RHaMBLe remote experiments and discusses them in their meteorological and chemical context as determined from these three platforms and from additional meteorological analyses. Air always arrived at the CVAO from the North East with a range of air mass origins (European, Atlantic and North American continental). Trace gases were present at stable and fairly low concentrations with the exception of a slight increase in some anthropogenic components in air of North American origin, though NOx mixing ratios during this period remained below 20 pptv (note the non-IUPAC adoption in this manuscript of pptv and ppbv, equivalent to pmol mol−1 and nmol mol−1 to reflect common practice). Consistency with these air mass classifications is observed in the time series of soluble gas and aerosol composition measurements, with additional identification of periods of slightly elevated dust concentrations consistent with the trajectories passing over the African continent. The CVAO is shown to be broadly representative of the wider North Atlantic marine boundary layer; measurements of NO, O3 and black carbon from the ship are consistent with a clean Northern Hemisphere marine background. Aerosol composition measurements do not indicate elevated organic material associated with clean marine air. Closer to the African coast, black carbon and NO levels start to increase, indicating greater anthropogenic influence. Lower ozone in this region is possibly associated with the increased levels of measured halocarbons, associated with the nutrient rich waters of the Mauritanian upwelling. Bromide and chloride deficits in coarse mode aerosol at both the CVAO and on D319 and the continuous abundance of inorganic gaseous halogen species at CVAO indicate significant reactive cycling of halogens. Aircraft measurements of O3 and CO show that surface measurements are representative of the entire boundary layer in the vicinity both in diurnal variability and absolute levels. Above the inversion layer similar diurnal behaviour in O3 and CO is observed at lower mixing ratios in the air that had originated from south of Cape Verde, possibly from within the ITCZ. ECMWF calculations on two days indicate very different boundary layer depths and aircraft flights over the ship replicate this, giving confidence in the calculated boundary layer depth

ARGONAUT II study of the in vitro activity of plazomicin against carbapenemase-producing klebsiella pneumoniae

Plazomicin was tested against 697 recently acquired carbapenemresistant Klebsiella pneumoniae isolates from the Great Lakes region of the United States. Plazomicin MIC50 and MIC90 values were 0.25 and 1 mg/liter, respectively; 680 isolates (97.6%) were susceptible (MICs of ≤2 mg/liter), 9 (1.3%) intermediate (MICs of 4 mg/liter), and 8 (1.1%) resistant (MICs of>32 mg/liter). Resistance was associated with rmtF-, rmtB-, or armA-encoded 16S rRNA methyltransferases in all except 1 isolate

Detection of internally deposited actinides. Part III. Recent background studies at ORNL

It has been apparent from accumulated data at ORNL that the low-energy (less than 100 keV) phoswich background spectrum in the iron-shielded counting facility has components, possibly including a line below 15 keV, whose magnitudes show considerable variability. We have used a planar intrinsic Ge detector designed especially for measuring low-energy photons for background study as part of an evaluation of such a device for in vivo $sup 239$Pu measurement. The spectrum that was observed consisted of a continuum upon which were superimposed discrete lines including a strong line at 10.35 keV in addition to the well-known lines from Pb X rays. Detectable also were X rays that corresponded to K-lines of several of the products of the naturally occurring radioactive decay series. Background spectra are presented and the implications of their variability are discussed. (auth

Testing, characterization, and control of a multi-axis high precision drive system for the Hobby-Eberle Telescope Wide Field Upgrade

A multi-axis, high precision drive system has been designed and developed for the Wide Field Upgrade to the Hobby-Eberly Telescope at McDonald Observatory. Design, performance and controls details will be of interest to designers of large scale, high precision robotic motion devices. The drive system positions the 20-ton star tracker to a precision of less than 5 microns along each axis and is capable of 4 meters of X/Y travel, 0.3 meters of hexapod actuator travel, and 46 degrees of rho rotation. The positioning accuracy of the new drive system is achieved through the use of high-precision drive hardware in addition to a meticulously tuned high-precision controller. A comprehensive understanding of the drive structure, disturbances, and drive behavior was necessary to develop the high-precision controller. Thorough testing has characterized manufacture defects, structural deflections, sensor error, and other parametric uncertainty. Positioning control through predictive algorithms that analytically compensate for measured disturbances has been developed as a result of drive testing and characterization. The drive structure and drive dynamics are described as well as key results discovered from testing and modeling. Controller techniques and development of the predictive algorithms are discussed. Performance results are included, illustrating recent performance of several axes of the drive system. This paper describes testing that occurred at the Center for Electromechanics in Austin Texas.Center for Electromechanic