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Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .

Backbone chemical shift assignments for the Toho-1 β-lactamase (263 amino acids, 28.9 kDa) are reported based on triple resonance solution-state NMR experiments performed on a uniformly 2H,13C,15N-labeled sample. These assignments allow for subsequent site-specific characterization at the chemical, structural, and dynamical levels. At the chemical level, titration with the non-β-lactam β-lactamase inhibitor avibactam is found to give chemical shift perturbations indicative of tight covalent binding that allow for mapping of the inhibitor binding site. At the structural level, protein secondary structure is predicted based on the backbone chemical shifts and protein residue sequence using TALOS-N and found to agree well with structural characterization from X-ray crystallography. At the dynamical level, model-free analysis of 15N relaxation data at a single field of 16.4 T reveals well-ordered structures for the ligand-free and avibactam-bound enzymes with generalized order parameters of ~ 0.85. Complementary relaxation dispersion experiments indicate that there is an escalation in motions on the millisecond timescale in the vicinity of the active site upon substrate binding. The combination of high rigidity on short timescales and active site flexibility on longer timescales is consistent with hypotheses for achieving both high catalytic efficiency and broad substrate specificity: the induced active site dynamics allows variously sized substrates to be accommodated and increases the probability that the optimal conformation for catalysis will be sampled.

After exposure to a traumatic event, a subset of people develop post-traumatic stress disorder (PTSD). One of the key deficits in PTSD is regulation of fear, and impaired inhibition of fear-potentiated startle (FPS) has been identified as a potential physiological biomarker specific to PTSD. As part of a larger clinical trial, this study investigated the effects of a CRF receptor 1 antagonist, GSK561679, on inhibition of fear-potentiated startle during a conditional discrimination fear-conditioning paradigm, termed AX+/BX-. Prior research using this paradigm has demonstrated deficits in inhibition of conditioned fear in several PTSD populations. The randomized, double-blind, placebo-controlled clinical trial compared fear inhibition between female PTSD participants taking 350 mg/day GSK561679 (n = 47 pre- and 29 post-treatment) and patients taking a placebo pill (n = 52 pre- and 30 post-treatment) daily for 6 weeks. There was no significant difference between the two groups in their acquisition of fear or discrimination between threat and safety cues, and no pre-post-treatment effect on these measures. However, there was a significant effect of treatment on inhibition of FPS during the AB trials in the AX+/BX- transfer test (p

BackgroundOvercoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa.MethodsIn this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer β-lactam/β-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO).ResultsWe found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA).ConclusionsThe diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.

Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second-order rate constant of the cycloaddition reaction can be up to 0.62 M-1 s-1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine-DIBAC and benzonorbornadiene-tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs.

BACKGROUND: We have previously evaluated the efficacy of the CRF1 receptor antagonist GSK561679 in female PTSD patients. While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers. Here, we test whether blood-based DNA methylation levels within CRHR1 and other PTSD-relevant genes would be associated with treatment outcome, either overall or in the high CRF activity subgroup. RESULTS: Therefore, we measured CRHR1 genotypes as well as baseline and post-treatment DNA methylation from the peripheral blood in the same cohort of PTSD-diagnosed women treated with GSK561679 (N = 43) or placebo (N = 45). In the same patients, we assessed DNA methylation at the PTSD-relevant genes NR3C1 and FKBP5, shown to predict or associate with PTSD treatment outcome after psychotherapy. We observed significant differences in CRHR1 methylation after GSK561679 treatment in the subgroup of patients with high CRF activity. Furthermore, NR3C1 baseline methylation significantly interacted with child abuse to predict PTSD symptom change following GSK561679 treatment. CONCLUSIONS: Our results support a possible role of CRHR1 methylation levels as an epigenetic marker to track response to CRF1 antagonist treatment in biologically relevant subgroups. Moreover, pre-treatment NR3C1 methylation levels may serve as a potential marker to predict PTSD treatment outcome, independent of the type of therapy. However, to establish clinical relevance of these markers, our findings require replication and validation in larger studies. TRIAL REGISTRATION: NCT01018992 . Registered 6 November 2009.

PURPOSE/BACKGROUND: For a drug to acquire Food and Drug Administration approval, it must significantly outperform placebo treatment. In recent years, the placebo effect seems to be increasing in neuropsychiatric conditions. Here, we examine placebo effects across self-reported, clinically rated, and performance-based data from a trial using a corticotropin-releasing hormone receptor type 1 (CRHR1) antagonist for treatment of post-traumatic stress disorder (PTSD). METHODS/PROCEDURES: Women with chronic PTSD were randomized to treatment with either GSK561679, a CRHR1 antagonist, or placebo. Before randomization, participants completed self-report scales, clinician-rated measures of PTSD and depression symptoms, and objective tests of cognition and functioning. Differences in change scores on measures were compared between GSK561679 and placebo-treated participants. FINDINGS/RESULTS: GSK561679 failed to produce any significant improvement in the participants. A substantial placebo effect was observed in both self-report and clinical rating scales, with effect sizes up to 1.5 SD. No single variable predicted placebo-related changes. Notably, there was an improvement on objective performance measures of cognition that exceeded previous standards for practice effects. IMPLICATIONS/CONCLUSIONS: Participants in this trial manifested retest effects on performance-based measures of cognition. Notably, they had minimal prior experience with performance-based assessments. Experiencing the structure and support of a clinical trial may have contributed to significant reductions in subject-reported and clinician-rated PTSD symptom levels. The improvement seen across all assessment domains was consistent with that seen in previous studies where the active treatments separated from placebo. Investigators conducting clinical trials treating PTSD patients should expect placebo effects and design studies accordingly.

Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, but alone it has no antianaerobic activity, with most anaerobes having MICs of ≥32 μg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem-resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.

BACKGROUND: Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD. METHODS: We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF1 receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period. RESULTS: In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF1 receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 (n = 6) but not with placebo (n = 7) on the PTSD Symptom Scale-Self-Report. CONCLUSIONS: The results of this trial, the first evaluating a CRF1 receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF1 receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF1 receptor antagonists lack efficacy as monotherapy agents for these conditions.

Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258 Klebsiella pneumoniae that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a nonfunctional OmpK35, whereas we demonstrate that a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced the activity of this porin and impacted ceftazidime-avibactam susceptibility. In addition, we demonstrate that the increased expression of blaKPC-3 and blaSHV-12 observed in the ceftazidime-avibactam-resistant isolate was due to transposition of the Tn4401 transposon harboring blaKPC-3 into a second plasmid, pIncX3, which also harbored blaSHV-12, ultimately resulting in a higher copy number of blaKPC-3 in the resistant isolate. pIncX3 plasmid from the ceftazidime-avibactam resistant isolate, conjugated into a OmpK35/36-deficient K. pneumoniae background that harbored a mutation to the ramR regulator of the acrAB efflux operon recreated the ceftazidime-avibactam-resistant MIC of 32 μg/ml, confirming that this constellation of mutations is responsible for the resistance phenotype.

Background: Z-drugs (hypnotics such as zolpidem, zopiclone, and zaleplon) and benzodiazepines (BZDs) are sedative medications with misuse liability. The goals of this study are to report the (1) prevalence of past-year any Z-drug use, any BZD use, and any BZD misuse by sexual identity category and psychological distress; (2) associations among these 3 categories between sexual identity and past-year psychological distress; (3) associations among these 3 categories with sexual identity by past-year psychological distress status., Methods: Data were collected from the National Survey on Drug Use and Health (years 2015-2019 [n = 210,392]), a yearly representative national household survey of the American population. We report prevalences of any Z-drug use, any BZD use, and any BZD misuse by sexual identity and past-year psychological distress status. We ran logistic regressions with complex survey design with the 3 dichotomous variables described above as the dependent variables, stratified and not-stratified by psychological distress., Results: Prevalence of any Z-drug an BZD use and any BZD misuse were higher among LGB (lesbian/gay/bisexual) populations, especially gay men and bisexual women. Psychological distress was positively associated with any Z-drug and BZD use and any BZD misuse. Women were at higher risk of Z-drug (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.18-1.37) and BZD use (OR, 1.64; 95% CI, 1.55-1.73), but lower risk of BZD misuse (OR, 0.82; 95% CI, 0.76-0.88). When stratifying by psychological distress, differences between LGB and heterosexuals were more pronounced among those without past-year psychological distress, especially gay men and bisexual women., Conclusions: The presence of psychological distress attenuates the disparities between LGB and heterosexual individuals in Z-drug use and BZD use and misuse., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

To perform first-in-human single-dose escalation trial of ZYKR1, which is a potent, selective, and peripherally-restricted kappa opioid receptor agonist, is the purpose of this study. This randomized, double-blind, placebo-controlled single ascending dose study conducted at Zydus Research Centre, Ahmedabad, India included healthy male participants aged 18-55 years and weighing > 50 kg. The primary objective was to evaluate the safety and tolerability of ZYKR1. The secondary objective was to evaluate the pharmacokinetics and pharmacodynamics (PD) of ZYKR1. Participants received ZYKR1 (0.5 - 6 mcg/kg) or placebo infused intravenously in 15 ± 1 min. Of total five dose groups (0.5 - 6 mcg/kg), each group included eight participants with six and two randomized to ZYKR1 and placebo, respectively. Three participants experienced six treatment-emergent adverse events (TEAEs); two were gastrointestinal disorders (nausea and vomiting at 2 mcg/kg); and four were related to the nervous system (headache (at 2 mcg/kg) and facial tingling, facial numbness and paresthesia (at 6 mcg/kg)); all TEAEs were mild and resolved without sequelae. The C max of ZYKR1 was achieved after 15 - 20 min of start of infusion. The mean exposures (C max and AUC 0 - t ) increased in a dose-proportional manner. The mean t 1/2 ranged from 2.20 to 2.98 h across the dose range. Increase in the mean prolactin level was significantly higher in treatment groups compared with that in the placebo group. Intravenous ZYKR1 at doses up to 6 mcg/kg showed acceptable safety and tolerability and demonstrated a short half-life with principal route of excretion as renal. ZYKR1 displayed a potent PD effect reflected by increased prolactin levels, supporting further study in patients. Trial registration Clinical Trial Registry of India: CTRI/2018/07/014927. Date of registration: 18/07/2018., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The emergence of multidrug-resistant Gram-negative bacilli and the development of new antibiotics have complicated the selection of optimal regimens. International guidelines are valuable tools, but are limited by the scarcity of high-quality randomized trials in many situations., Methods: A panel of experts from the French and Italian Societies of Infectious Diseases aimed to address unresolved issues in clinical practice based on their experience, an updated literature review and open discussions., Results: The panel reached consensus for the following 'first choices': (i) cefepime for ventilator-acquired pneumonia due to AmpC β-lactamase-producing Enterobacterales; (ii) the β-lactam/β-lactamase inhibitor combination most active in vitro, or cefiderocol combined with fosfomycin, and aerosolized colistin or aminoglycosides, for severe pneumonia due to Pseudomonas aeruginosa resistant to ceftolozane-tazobactam; (iii) high-dose piperacillin-tazobactam (including loading dose and continuous infusion) for complicated urinary tract infections (cUTIs) caused by extended-spectrum β-lactamase-producing Enterobacterales with piperacillin-tazobactam minimum inhibitory concentration (MIC) ≤8 mg/L; (iv) high-dose cefepime for cUTIs due to AmpC β-lactamase-producing Enterobacterales other than Enterobacter spp. if cefepime MIC ≤2 mg/L; (v) ceftolozane-tazobactam or ceftazidime-avibactam plus metronidazole for intra-abdominal infections (IAIs) due to third-generation cephalosporin-resistant Enterobacterales; (vi) ceftazidime-avibactam plus aztreonam plus metronidazole for IAIs due to metallo-β-lactamase-producing Enterobacterales; (vii) ampicillin-sulbactam plus colistin for bloodstream infections (BSIs) caused by carbapenem-resistant Acinetobacter baumannii; (viii) meropenem-vaborbactam for BSIs caused by Klebsiella pneumoniae carbapenemase-producing Enterobacterales; and (ix) ceftazidime-avibactam plus fosfomycin for neurological infections caused by carbapenem-resistant P. aeruginosa., Conclusions: These expert choices were based on the necessary balance between antimicrobial stewardship principles and the need to provide optimal treatment for individual patients in each situation., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

IntroductionAQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia.MethodsThis was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial (NCT00825539) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5mg, 50mg or 100mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability.ResultsOverall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5mg n=9; 50mg n=11; 100mg n=10. Placebo then AQW051: 7.5mg n=10; 50mg n=11; 100mg n=9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100mg versus placebo (0.431; p=0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p=0.007) and a medium effect size in the posterior hippocampus (0.476; p=0.079) with AQW051 7.5mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile.ConclusionsOverall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia.

This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to

Ceftazidime-avibactam (CZA) resistance is a huge threat in the clinic; however, the underlying mechanism responsible for high-level CZA resistance in Pseudomonas aeruginosa (PA) isolates remains unknown. In this study, a total of 5,763 P. aeruginosa isolates were collected from 2010 to 2022 to investigate the ceftazidime-avibactam (CZA) high-level resistance mechanisms of Pseudomonas aeruginosa (PA) isolates in China. Fifty-six PER-producing isolates were identified, including 50 isolates carrying bla PER-1 in PA, and 6 isolates carrying bla PER-4 . Of these, 82.1% (46/56) were classified as DTR-PA isolates, and 76.79% (43/56) were resistant to CZA. Importantly, bla PER-1 and bla PER-4 overexpression led to 16-fold and >1024-fold increases in the MICs of CZA, respectively. WGS revealed that the bla PER-1 gene was located in two different transferable IncP-2-type plasmids and chromosomes, whereas bla PER-4 was found only on chromosomes and was carried by a class 1 integron embedded in a Tn 6485 -like transposon. Overexpression of efflux pumps may be associated with high-level CZA resistance in bla PER-1 -positive strains. Kinetic parameter analysis revealed that PER-4 exhibited a similar kcat / Km with ceftazidime and a high (∼3359-fold) IC50 value with avibactam compared to PER-1. Our study found that overexpression of PER-1 combined with enhanced efflux pump expression and the low affinity of PER-4 for avibactam contributes to high-level resistance to CZA. Additionally, the Tn 6485 -like transposon plays a significant role in disseminating bla PER . Urgent active surveillance is required to prevent the further spread of high-level CZA resistance in DTR-PA isolates.

Serotonin 5-HT3 receptors are involved in various brain functions including as an emesis target during cancer chemotherapy. We report here the development of (S)-2,3-dimethoxy-5-(3'-[(18)F]fluoropropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide ([(18)F]fesetron) as a potential PET imaging agent for serotonin 5-HT3 receptors. By radiolabeling((S)-2,3-dimethoxy-5-(3'-tosyloxypropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide) with fluorine-18, (S)-[(18)F]fesetron was obtained in 5 to 10% decay-corrected yields and with specific activities >74GBq/μmol at the end of radiosynthesis. PET imaging in rats showed low uptake of [(18)F]fesetron in the brain with retention of binding in the striatal and cerebellar regions. Using colliculi as a reference region, ratios were 3.4 for striata and 2.5 for cerebellum. Ex vivo brain PET analysis displayed binding of [(18)F]fesetron in the hippocampus, striatum and cerebellar regions. Cerebellar regions corresponded to area postrema and nucleus tract solitaris known to contain 5-HT3 receptors. Dorsal hippocampus showed the highest uptake with ratio of >17 with respect to colliculi, while area postrema and striata had ratios of >10. Thus, [(18)F]fesetron exhibited a unique binding profile to rat brain regions known to contain significant amounts of serotonin 5-HT3 receptors. However, the very low brain uptake limits its usefulness as a PET radiotracer in this animal model.

Ceftazidime-avibactam is the first antimicrobial approved by the U.S. FDA for the treatment of carbapenem-resistant Enterobacteriaceae. Avibactam, a non-β-lactam β-lactamase inhibitor, inactivates class A serine carbapenemases, including Klebsiella pneumoniae carbapenemase (KPC). We report a KPC-producing K. pneumoniae isolate resistant to ceftazidime-avibactam (MIC, 32/4 μg/ml) from a patient with no prior treatment with ceftazidime-avibactam.

A man in his 40s with type 2 diabetes mellitus had persistent right-sided watery nasal discharge for 6 months following cerebrospinal fluid (CSF) leak repair at another hospital, prompting his visit to us due to recurring symptoms. Imaging revealed a CSF leak from the mid-clivus for which revision endoscopic CSF leak repair was done. Regrettably, he developed postoperative meningitis caused by multidrug-resistant (MDR) Klebsiella pneumoniae Managing this complex case was a challenging task due to the pathogen's resistance to conventional drugs and the scarcity of scientific evidence. We initiated a culture-guided combination regimen with ceftazidime, avibactam, aztreonam and tigecycline. This decision stemmed from meticulous literature review and observed antibiotic synergy while testing for this organism.After 4 weeks of vigilant treatment, the patient's symptoms improved significantly, and CSF cultures were sterile. We present our approach to effectively confront and manage a challenging instance of postoperative MDR bacterial meningitis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent years, pyclen-based complexes have attracted a great deal of interest as magnetic resonance imaging (MRI) contrast agents (CAs) and luminescent materials, as well as radiopharmaceuticals. Remarkably, gadopiclenol, a Gd(III) bishydrated complex featuring a pyclen-based heptadentate ligand, received approval as a novel contrast agent for clinical MRI application in 2022. To maximize stability and efficiency, two novel chiral pyclen-based chelators and their complexes were developed in this study. Gd-X-PCTA-2 showed significant enhancements in both thermodynamic and kinetic stabilities compared to those of the achiral parent derivative Gd-PCTA . 1 H NMRD profiles reveal that both chiral gadolinium complexes ( Gd-X-PCTA-1 and Gd-X-PCTA-2 ) have a higher relaxivity than Gd-PCTA , while variable-temperature 17 O NMR studies show that the two inner-sphere water molecules have distinct residence times τ M a and τ M b . Furthermore, in vivo imaging demonstrates that Gd-X-PCTA-2 enhances the signal in the heart and kidneys of the mice, and the chiral Gd complexes exhibit the ability to distinguish between tumors and normal tissues in a 4T1 mouse model more efficiently than that of the clinical agent gadobutrol. Biodistribution studies show that Gd-PCTA and Gd-X-PCTA-2 are primarily cleared by a renal pathway, with 24 h residues of Gd-X-PCTA-2 in the liver and kidney being lower than those of Gd-PCTA .

Background: Multi/extensively drug-resistant bacterial infections have recently increased and new antimicrobial options are needed for difficult-to-treat infections. Ceftazidime/avibactam (CZA) has been approved for patients 3 months to 18 years of age, but real-life data on its off-label use in neonates and young infants are still scarce., Materials: We report demographic, clinical and microbiologic data as well as outcome and safety of all cases of infants treated with CZA between January 1, 2021 and September 30, 2022 in a tertiary neonatal intensive care unit. We also review all neonatal cases previously reported., Results: Twenty-one patients [17 males, with median gestational age 29 +2 (IQR 6 +6 ) weeks] received 31 CZA courses at a dose of 20-50 mg/kg/dose of ceftazidime q8h for suspected or proved multi/extensively drug-resistant infections. Median postnatal age at the onset of treatment was 44 days (IQR: 94 days). Twelve bacteremias, 2 urinary tract infections and 1 ventilator-acquired pneumonia were recorded. Twelve (39%) treatments were targeted, while 19 (61%) were empirically started due to known colonization with Klebsiella pneumoniae carbapenemase-producing Gram-negative bacteria. All patients had received multiple antibiotics prior and concomitantly with CZA. The most common pathogen identified at targeted administrations was carbapenem-resistant Klebsiella pneumoniae (83%). No serious adverse events attributed to the drug were detected. Twenty-one courses of CZA administration to 20 neonates with a median gestational age of 28.5 (IQR 3.5) weeks were previously reported without significant related adverse events., Conclusions: Favorable clinical and microbiologic responses in neonatal intensive care unit patients treated with CZA off-label were observed without significant and unexpected adverse events in critically ill neonates., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a substantial healthcare challenge. This study assessed the in vitro efficacy of selected antibiotic combinations against CRKP infections., Methods: Our research involved the evaluation of 40 clinical isolates of CRKP, with half expressing Klebsiella pneumoniae carbapenemase (KPC) and half producing Metallo-β-lactamase (MBL), two key enzymes contributing to carbapenem resistance. We determined the minimum inhibitory concentrations (MICs) of four antibiotics: eravacycline, tigecycline, polymyxin-B, and ceftazidime/avibactam. Synergistic interactions between these antibiotic combinations were examined using checkerboard and time-kill analyses., Results: We noted significant differences in the MICs of ceftazidime/avibactam between KPC and MBL isolates. Checkerboard analysis revealed appreciable synergy between combinations of tigecycline (35%) or eravacycline (40%) with polymyxin-B. The synergy rates for the combination of tigecycline or eravacycline with polymyxin-B were similar among the KPC and MBL isolates. These combinations maintained a synergy rate of 70.6% even against polymyxin-B resistant isolates. In contrast, combinations of tigecycline (5%) or eravacycline (10%) with ceftazidime/avibactam showed significantly lower synergy than combinations with polymyxin-B (P < 0.001 and P = 0.002, respectively). Among the MBL CRKP isolates, only one exhibited synergy with eravacycline or tigecycline and ceftazidime/avibactam combinations, and no synergistic activity was identified in the time-kill analysis for these combinations. The combination of eravacycline and polymyxin-B demonstrated the most promising synergy in the time-kill analysis., Conclusion: This study provides substantial evidence of a significant synergy when combining tigecycline or eravacycline with polymyxin-B against CRKP strains, including those producing MBL. These results highlight potential therapeutic strategies against CRKP infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bacterial resistance surveillance is one of the main outputs of microbiological laboratories and its results are important part of antimicrobial stewardship (AMS). In this study, the susceptibility of specific bacteria to selected antimicrobial agents was tested. The susceptibility of 90 unique isolates of pathogens of critical priority obtained from clinically valid samples of ICU patients in 2017-2021 was tested. 50% of these fulfilled difficult-to-treat resistance (DTR) criteria and 50% were susceptible to all antibiotics included in the definition. 10 Enterobacterales strains met DTR criteria, and 2 (20%) were resistant to colistin (COL), 2 (20%) to cefiderocol (FCR), 7 (70%) to imipenem/cilastatin/relebactam (I/R), 3 (30%) to ceftazidime/avibactam (CAT) and 5 (50%) to fosfomycin (FOS). For Enterobacterales we also tested aztreonam/avibactam (AZA) for which there are no breakpoints yet. The highest MIC of AZA observed was 1 mg/l, MIC range in the susceptible cohort was 0.032-0.064 mg/l and in the DTR cohort (incl. class B beta-lactamase producers) it was 0.064-1 mg/l. Two (13.3%) isolates of Pseudomonas aeruginosa (15 DTR strains) were resistant to COL, 1 (6.7%) to FCR, 13 (86.7%) to I/R, 5 (33.3%) to CAT, and 5 (33.3%) to ceftolozane/tazobactam. All isolates of Acinetobacter baumannii with DTR were susceptible to COL and FCR, and at the same time resistant to I/R and ampicillin/sulbactam. New antimicrobial agents are not 100% effective against DTR. Therefore, it is necessary to perform susceptibility testing of these antibiotics, use the data for surveillance (including local surveillance) and conform to AMS standards., (© 2024. The Author(s).)

Carbapenem resistance due to metallo-β-lactamases (MBLs) such as the Verona integron-encoded metallo-β-lactamase (VIM) is particularly problematic due to the limited treatment options. We describe a case series of bacterial infections in a tertiary care hospital due to multi-species acquisition of a VIM gene along with our experience using novel β-lactam antibiotics and antibiotic combinations to treat these infections. Four patients were treated with the combination of ceftazidime-avibactam and aztreonam, with no resistance to the combination detected. However, cefiderocol-resistant Klebsiella pneumoniae isolates were detected in two out of the five patients who received cefiderocol within 3 weeks of having started the antibiotic. Strain pairs of sequential susceptible and resistant isolates from both patients were analyzed using whole-genome sequencing. This analysis revealed that the pairs of isolates independently acquired point mutations in both the cirA and fiu genes, which encode siderophore receptors. These point mutations were remade in a laboratory strain of K. pneumoniae and resulted in a significant increase in the MIC of cefiderocol, even in the absence of a beta-lactamase enzyme or a penicillin-binding protein 3 (PBP3) mutation. While newer β-lactam antibiotics remain an exciting addition to the antibiotic armamentarium, their use must be accompanied by diligent monitoring for the rapid development of resistance., Competing Interests: T.R.T. is on the Board of Directors for OmniSolve R.M.H. has provided consulting for AbbVie E.P.S. is on the Scientific Advisory Board for Pfizer Vaccines

Ceftazidime-avibactam and cefiderocol represent two of the few alternatives for infections by KPC-producing Enterobacterales. We reported the emergence of resistance to both ceftazidime-avibactam and cefiderocol in a KPC-producing ST131- Escherichia coli (KPC-ST131- Ec ) clinical isolate. Antimicrobial susceptibility testing, Fourier-transform infrared (FTIR) spectroscopy, whole-genome sequencing, and cloning experiments were performed. A KPC-49- Ec isolate resistant to ceftazidime-avibactam (MIC CZA > 16/4 mg/L) and susceptible to cefiderocol (MIC FDC : 2 mg/L) was recovered in a blood sample from an oncologic patient hospitalized in the medical ICU (June 2019) during ceftazidime-avibactam treatment. After 44 days, a KPC-31- Ec resistant to both ceftazidime-avibactam and cefiderocol (MIC CZA > 16/4 mg/L, MIC FDC : 8 mg/L) was found in a rectal sample during a second cycle of ceftazidime-avibactam treatment. Both KPC-49 (R163S) and KPC-31 (D179Y) were detected in the epidemic ST131-H30R1- Ec high-risk clone and showed a phenotype resembling that of ESBL producers. FTIR spectroscopy managed to differentiate cefiderocol-susceptible and resistant ST131- Ec isolates, and these from others belonging to different clones. After cloning and transformation experiments, KPC-49 and KPC-31 were responsible for ceftazidime-avibactam resistance (MIC CZA > 16/4 mg/L) and decreased carbapenem MICs (MIC MER ≤ 0.12 mg/L, MIC IMI ≤ 1 mg/L). KPC-31 was also shown to be associated with increased MICs of cefiderocol (twofold and threefold dilutions over KPC-3 and KPC-49, respectively). However, mutations in proteins participating in outer membrane stability and integrity, such as TolR, could have a more relevant role in cefiderocol resistance. The effects of ceftazidime-avibactam and cefiderocol co-resistance in clinical isolates of Enterobacterales producing KPC mutants make their identification challenging for clinical laboratories.IMPORTANCEThroughout four admissions in our hospital of a single patient, different KPC-3 variants (KPC-3, KPC-49, and KPC-31) were found in surveillance and clinical ST131- Escherichia coli isolates, after prolonged therapies with meropenem and ceftazidime-avibactam. Different patterns of resistance to cefiderocol and ceftazidime-avibactam emerged, accompanied by restored carbapenem susceptibility. The inability to detect these variants with some phenotypic methods, especially KPC-31 by immunochromatography, and the expression of a phenotype similar to that of ESBL producers, posed challenge to identify these variants in the clinical microbiology laboratory. Molecular methods and whole-genome sequencing are necessary and new techniques able to cluster or differentiate related isolates could also be helpful; this is the case of Fourier-transform infrared spectroscopy, which managed in our study to discriminate isolates by cefiderocol susceptibility within ST131, and those from the non-ST131 ones., Competing Interests: The authors declare no conflict of interest.

The combination of ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) is used to treat MBL-producing Enterobacterales-related infections. The new combination aztreonam-avibactam (AZA) is currently in development. We compared results obtained with the new MIC test strip (MTS) AZA (Liofilchem) with broth microdilution method (BMD) on 41 MBL-producing Enterobacterales from 41 clinical samples. The MTS AZA was also compared to combination testing method using CAZ-AVI and ATM strips. Compared to BMD, categorical agreement (CA) was 100%. Compared with combination testing method, CA was 97.6%. The MTS AZA can be used to determine MICs levels of AZA or CAZ-AVI/ATM combinations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In last years the diffusion of carbapenem resistance in Gram-negative bacteria (CR-GNB) is increasing worldwide, mainly due to the expression of carbapenemases. Cefiderocol has molecular characteristics that ideally confers activity against all CR-GNB, but resistant strains have already been identified. We describe cefiderocol susceptibility profile among multi-drug resistant Gram-negative isolated from pediatric patients., Methods: Prospective, single pediatric center study, 1st January 2020-15th June 2023. All GNB carbapenemases producers or phenotypically carbapenem-resistant isolated in the study period were tested for cefiderocol susceptibility. Clinical and microbiological data were collected. A descriptive analysis was performed, comparing the groups of cefiderocol-resistant vs. cefiderocol-susceptible Enterobacterales and non-fermenting Gram-negative bacteria (NF-GNB)., Results: Forty-seven GNB were tested for cefiderocol susceptibility; 38% were cefiderocol-resistant: 16/30 (52%) among Enterobacterales and 2/17 (12%) among NF-GNB. None of the patients were previously exposed to cefiderocol. Looking at Enterobacterales, resistance to ceftazidime/avibactam was higher among cefiderocol-resistant vs. cefiderocol-susceptible strains (62% vs 36%, respectively), as MBL expression (67% vs. 36%, respectively). Too few NF-GNB were cefiderocol-resistance to draw any conclusion. No difference in ICU admission and mortality was identified comparing cefiderocol-resistant vs. susceptible strains. Patients colonized/infected by cefiderocol-resistant strains had been previously hospitalized more frequently., Conclusion: In our cohort cefiderocol resistance was mostly registered among Enterobacterales, and especially among MBL producers' strains (that were alongside resistant to ceftazidime/avibactam). This could be explained by the known possible cross resistance mechanism among ceftazidime/avibactam and cefiderocol. Also, correlation of cefiderocol-resistance with previous hospitalization could be associated with horizontal resistance transmission. Looking at our data, we believe that cefiderocol should be use cautiously, especially empirically and in monotherapy, due to the high resistance rate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections., Methods: Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection., Results: Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies., Conclusion: A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program., Clinical Trial Registration: NCT01689207; NCT02655419; NCT03329092; NCT03580044., (© 2024. The Author(s).)

The aim of this study was to prepare a drug carrier that could deliver oral insulin to the intestine. A hydrogel beads composed of sodium carboxymethyl cellulose (CMC), Zingiber offtcinale polysaccharide (ZOP) and chitosan (CS) were prepared by ionic gel method as insulin carrier. Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), Scanning electron microscopy (SEM) and thermogravimetric (TGA) showed that the hydrogel was formed by metal ion coordination between ZOP and CMC and Fe 3+ , and CS was coated on the surface of the hydrogel ball in the form of non covalent bond. The results showed that the swelling process of hydrogel spheres has significant pH sensitivity. In addition, the hydrogel beads successfully coated insulin, and the drug loading rate (DL) of (ZOP/CMC-Fe 3+ )@CS could reach 69.43 ± 7.32 mg/g, and the entrapment efficiency (EE) could reach 66.94 ± 7.43 %. In vitro release experiments, the release rate of (CMC/ZOP-Fe 3+ )@CS in simulated gastric fluid (SGF) for 2 h was <20 %, and the cumulative release rate of insulin after 9 h in simulated intestinal fluid (SIF) reached over 90 %. The results showed that the hydrogel beads prepared in this work could be used as a potential carrier for delivering oral insulin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections commonly cause hospital-acquired infections. The study aimed to compare the outcomes of CRKP infections between patients receiving ceftazidime avibactam +/- aztreonam and polymyxins in a hospital setting with a high prevalence of New Delhi Metallo Beta Lactamase production., Methods: We conducted a retrospective cohort study from January 2020 to September 2022 in critically ill adult patients admitted to a non-COVID-19 medical intensive care unit with CRKP infection. The patients were followed up for a total of 30 days or death, whichever was later., Results: Of a total of 106 patients included in the study, 65 patients received polymyxins and 41 patients received ceftazidime-avibactam +/- aztreonam. Higher 30-day mortality was noted in the polymyxin group (56.9% vs. 29.2%, P = 0.005). The mean time to event (mortality) in ceftazidime-avibactam +/- aztreonam was 23.9 + 1.5 days which was significantly higher compared to polymyxins (17.9 + 1.2 days, p = 0.006). On Cox regression analysis, after adjusting for the covariates, the hazard ratio for time to event with the use of polymyxin was 2.02 (95% CI: 1.03-3.9)., Conclusion: Ceftazidime-avibactam + aztreonam is possibly associated with better clinical outcomes in patients infected with CRKP., (© 2023. The Author(s).)

BackgroundInsomnia is frequent in schizophrenia and may contribute to cognitive impairment as well as overuse of weight inducing sedative antipsychotics. We investigated the effects of eszopiclone on sleep and cognition for patients with schizophrenia-related insomnia in a double-blind placebo controlled study, followed by a two-week, single-blind placebo phase.MethodsThirty-nine clinically stable outpatients with schizophrenia or schizoaffective disorder and insomnia were randomized to either 3mg eszopiclone (n=20) or placebo (n=19). Primary outcome measure was change in Insomnia Severity Index (ISI) over 8 weeks. Secondary outcome measure was change in MATRICS Consensus Cognitive Battery (MATRICS). Sleep diaries, psychiatric symptoms, and quality of life were also monitored.ResultsISI significantly improved more in eszopiclone (mean=-10.7, 95% CI=-13.2; -8.2) than in placebo (mean=-6.9, 95% CI=-9.5; -4.3) with a between-group difference of -3.8 (95% CI=-7.5; -0.2). MATRICS score change did not differ between groups. On further analysis there was a significant improvement in the working memory test, letter-number span component of MATRICS (mean=9.8±9.2, z=-2.00, p=0.045) only for subjects with schizophrenia on eszopiclone. There were improvements in sleep diary items in both groups with no between-group differences. Psychiatric symptoms remained stable. Discontinuation rates were similar. Sleep remained improved during single-blind placebo phase after eszopiclone was stopped, but the working memory improvement in patients with schizophrenia was not durable.ConclusionsEszopiclone stands as a safe and effective alternative for the treatment of insomnia in patients with schizophrenia. Its effects on cognition require further study.