scholarly journals 1110. In Vivo Pharmacodynamics of Vancomycin Against Staphylococci in Young Infants

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S646-S647
Author(s):  
Amanda Gwee ◽  
Stephen Duffull ◽  
Derek Zhu
Keyword(s):  
Late Onset ◽  
Area Under The Curve ◽  
Bloodstream Infections ◽  
Fold Increase ◽  
Broth Microdilution ◽  
Coagulase Negative Staphylococci ◽  
Bacteriological Cure ◽  
Young Infants ◽  
Predominant Pathogen

Abstract Background Coagulase-negative staphylococci are the predominant pathogen causing late onset sepsis in young infants, however, the pharmacodynamic target for vancomycin therapy is unknown. This study aimed to determine the pharmacodynamic target of vancomycin in young infants with staphylococcal infections. Methods Retrospective data were collected for infants aged 0-90 days with methicillin-resistant Staphylococcus aureus (MRSA or coagulase-negative staphylococci (CoNS) bacteraemia over a 4-year period at the Royal Children’s Hospital Melbourne, Australia. Vancomycin broth microdilution minimum inhibitory concentrations (MIC) were determined. A published pharmacokinetic model was externally validated using the study dataset and a time-to-event pharmacodynamic model developed using non-linear mixed effects modelling, with the event being the first negative blood culture. Simulations were performed to determine the 24-hour trough vancomycin concentration correlating with a 90% probability target attainment (PTA) of the area under the curve in the first 24-hours (AUC0-24) exceeding the identified target. Results Thirty infants, 28 with CoNS and two with MRSA bacteraemia, who had 165 vancomycin concentrations determined were included. The vancomycin broth microdilution MIC was determined for 24 CoNS and one MRSA isolate, both with a median MIC of 1 mg/L (CoNS range 0.5 to 4). An AUC0-24 ≥3 00 mg/L·h was associated with a 7.8-fold increase in the chance of bacteriological cure for all staphylococci at any time point compared to an AUC0-24 < 300 mg/L·h (hazard ratio 95% CI: 3.21-18.8). The 24-hour trough concentrations associated with a 90% PTA of achieving this target were > 13-16 mg/L and > 8-12 mg/L for 6 and 12-hourly dosing, respectively. Conclusion Our study found that an AUC0-24 ≥ 300 mg/L·h was associated with a 7.8-fold increase in bacteriological cure in young infants with staphylococcal bloodstream infections. Disclosures All Authors: No reported disclosures

scholarly journals Bottlebrush-architectured poly(ethylene glycol) as an efficient vector for RNA interference in vivo

2019 ◽  
Vol 5 (2) ◽  
pp. eaav9322 ◽  
Author(s):  
Dali Wang ◽  
Jiaqi Lin ◽  
Fei Jia ◽  
Xuyu Tan ◽  
Yuyan Wang ◽  
...  
Keyword(s):  
Rna Interference ◽  
Ethylene Glycol ◽  
Target Genes ◽  
Area Under The Curve ◽  
Fold Increase ◽  
Small Interfering Rnas ◽  
Poly Ethylene Glycol ◽  
Linear Poly ◽  
Poly Ethylene

Nonhepatic delivery of small interfering RNAs (siRNAs) remains a challenge for development of RNA interference–based therapeutics. We report a noncationic vector wherein linear poly(ethylene glycol) (PEG), a polymer generally considered as inert and safe biologically but ineffective as a vector, is transformed into a bottlebrush architecture. This topology provides covalently embedded siRNA with augmented nuclease stability and cellular uptake. Consisting almost entirely of PEG and siRNA, the conjugates exhibit a ~25-fold increase in blood elimination half-life and a ~19-fold increase in the area under the curve compared with unmodified siRNA. The improved pharmacokinetics results in greater tumor uptake and diminished liver capture. Despite the structural simplicity these conjugates efficiently knock down target genes in vivo without apparent toxic and immunogenic reactions. Given the benign biological nature of PEG and its widespread precedence in biopharmaceuticals, we anticipate the brush polymer–based technology to have a significant impact on siRNA therapeutics.

Evaluation of in vitro susceptibility of Gram-positive pathogens from a tertiary care hospital in Singapore to a novel oxazolidinone, tedizolid, by a gradient diffusion method and broth microdilution

2018 ◽  
Vol 72 (2) ◽  
pp. 181-184
Author(s):  
Saugata Choudhury ◽  
Lee Kar Mun ◽  
Esme Ng Chu Xuan ◽  
Lee Shin Jia ◽  
Shawn Vasoo ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Bloodstream Infections ◽  
Diffusion Method ◽  
Care Hospital ◽  
Broth Microdilution ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
In Vitro Susceptibility ◽  
Gradient Diffusion

We compared the in vitro antimicrobial activities of tedizolid and linezolid on the Sensititre broth microdilution system for Gram-positive cocci isolates (n=146) from skin and skin structure infections and bloodstream infections, bronchoalveolar lavage and sputum. These pathogens included 40 methicillin-resistant Staphylococcus aureus, 38 coagulase-negative staphylococci, 20 Enterococcus faecalis and 48 beta-haemolytic Streptococcus spp. Susceptibility was simultaneously determined for 48 vanA vancomycin-resistant enterococci isolates 2013–2016 from rectal swabs (23 E. faecalis and 25 E. faecium, of which 4 were linezolid-non-susceptible). MIC90s for tedizolid were fourfold to eightfold lower than linezolid on the Sensititre and ranged from 0.12 to 0.5 µg/mL for the different pathogen groups. All isolates were susceptible to tedizolid except two vanA E. faecium strains (MICs of 1 and 2 µg/mL, respectively). Categorical and essential agreement for tedizolid were 99.48% and 92%, respectively, between Liofilchem gradient diffusion and Sensititre methods. Overall, the drug exhibited excellent activity against the surveyed Gram-positive pathogens.

scholarly journals The Profile of Microorganisms Responsible for Port-Related Bacteremia in Pediatric Hemato-Oncological Patients

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482090469
Author(s):  
Ewelina Gowin ◽  
Bogna Świątek-Kościelna ◽  
Przemysław Mańkowski ◽  
Danuta Januszkiewicz-Lewandowska
Keyword(s):  
Medical Records ◽  
Bloodstream Infections ◽  
Venous Catheter ◽  
Complete Information ◽  
Incidence Density ◽  
Coagulase Negative Staphylococci ◽  
Patients With Cancer ◽  
Oncological Patients ◽  
Increased Risk ◽  
Predominant Pathogen

Patients with pediatric cancer face an increased risk of infections. In most cases, these infections are associated with the use of a long-term central venous catheter. This study describes the epidemiology of a port-associated bacteremia as well as a profile of microorganisms responsible for port-associated bloodstream infections (PABSIs) in pediatric patients with cancer treated in a single center. The retrospective analysis included patients with cancer who had implanted a port, hospitalized between 2010 and 2015 at the Department of Pediatric Oncology, Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences. The medical records of patients were reviewed for demographic characteristics, diagnosis, port-related complications, and their management. Data were collected from patients’ electronic medical records containing complete information on medical examinations and supplementary tests, diagnosis, timing, and type of port-associated complications. In a study period, 277 ports were inserted to 241 patients. A total of 183 094 catheter days were analyzed. Sixteen patients had more than 1 insertion of a port. The commonest observed complication was PABSI (40.07%) and the incidence density was 0.6 per 1000 port-days. Staphylococcus was the most commonly isolated organisms from patients with PABSI. From all port-associated complications, bloodstream infections and mechanical complications were the most often observed complications. The commonest pathogens responsible for PABSI were coagulase-negative staphylococci. Pathogens resistant to standard antibiotic treatment play an important role in PABSI, with methicillin-resistant Staphylococcus epidermidis being the predominant pathogen. Port-associated bloodstream infections are a common reason for preterm removal of a port.

scholarly journals Enhanced cAMP generation and insulin-releasing potency of two novel Tyr1-modified enzyme-resistant forms of glucose-dependent insulinotropic polypeptide is associated with significant antihyperglycaemic activity in spontaneous obesity-diabetes

2002 ◽  
Vol 367 (3) ◽  
pp. 913-920 ◽  
Author(s):  
Victor A. GAULT ◽  
Peter R. FLATT ◽  
Clifford J. BAILEY ◽  
Patrick HARRIOTT ◽  
Brett GREER ◽  
...  
Keyword(s):  
Type Ii Diabetes ◽  
Chinese Hamster ◽  
Area Under The Curve ◽  
Fold Increase ◽  
Type Ii Diabetes Mellitus ◽  
Type Ii ◽  
Dpp Iv ◽  
Camp Generation

Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin hormone, which potentiates glucose-induced insulin secretion. Antihyperglycaemic actions of GIP provide significant potential in Type II diabetes therapy. However, inactivation of GIP by the enzyme dipeptidyl peptidase IV (DPP IV) and its consequent short circulating half-life limit its therapeutic use. Therefore two novel Tyr1-modified analogues of GIP, N-Fmoc-GIP (where Fmoc is 9-fluorenylmethoxycarbonyl) and N-palmitate-GIP, were synthesized and tested for metabolic stability and biological activity. Both GIP analogues were resistant to degradation by DPP IV and human plasma. In Chinese hamster lung (CHL) cells expressing the cloned human GIP receptor, both analogues exhibited a 2-fold increase in cAMP-generating potency compared with native GIP (EC50 values of 9.4, 10.0 and 18.2nM respectively). Using clonal BRIN-BD11 cells, both analogues demonstrated strong insulinotropic activity compared with native GIP (P<0.01 to P<0.001). In obese diabetic (ob/ob) mice, administration of N-Fmoc-GIP or N-palmitate-GIP (25nmol/kg) together with glucose (18mmol/kg) significantly reduced the peak 15min glucose excursion (1.4- and 1.5-fold respectively; P<0.05 to P<0.01) compared with glucose alone. The area under the curve (AUC) for glucose was significantly lower after administration of either analogue compared with glucose administered alone or in combination with native GIP (1.5-fold; P<0.05). This was associated with a significantly greater AUC for insulin (2.1-fold; P<0.001) for both analogues compared with native GIP. A similar pattern of in vivo responsiveness was evident in lean control mice. These data indicate that novel N-terminal Tyr1 modification of GIP with an Fmoc or palmitate group confers resistance to degradation by DPP IV in plasma, which is reflected by increased in vitro potency and greater insulinotropic and antihyperglycaemic activities in an animal model of Type II diabetes mellitus.

National Bloodstream Infection Surveillance in Switzerland 2008–2014: Different Patterns and Trends for University and Community Hospitals

2016 ◽  
Vol 37 (9) ◽  
pp. 1060-1067 ◽  
Author(s):  
Niccolò Buetti ◽  
Jonas Marschall ◽  
Andrew Atkinson ◽  
Andreas Kronenberg ◽  
Keyword(s):  
Bloodstream Infection ◽  
Bloodstream Infections ◽  
Community Hospitals ◽  
University Hospitals ◽  
Coagulase Negative Staphylococci ◽  
E Coli ◽  
Infection Surveillance ◽  
Laboratory Surveillance ◽  
Predominant Pathogen ◽  
Hospital Acquired

OBJECTIVETo characterize the epidemiology of bloodstream infections in Switzerland, comparing selected pathogens in community and university hospitals.DESIGNObservational, retrospective, multicenter laboratory surveillance study.METHODSData on bloodstream infections from 2008 through 2014 were obtained from the Swiss infection surveillance system, which is part of the Swiss Centre for Antibiotic Resistance (ANRESIS). We compared pathogen prevalences across 26 acute care hospitals. A subanalysis for community-acquired and hospital-acquired bloodstream infections in community and university hospitals was performed.RESULTSA total of 42,802 bloodstream infection episodes were analyzed. The most common etiologies were Escherichia coli (28.3%), Staphylococcus aureus (12.4%), and polymicrobial bloodstream infections (11.4%). The proportion of E. coli increased from 27.5% in 2008 to 29.6% in 2014 (P = .04). E. coli and S. aureus were more commonly reported in community than university hospitals (34.3% vs 22.7%, P<.001 and 13.9% vs 11.1%, P<.001, respectively). Fifty percent of episodes were community-acquired, with E. coli again being more common in community hospitals (41.0% vs 32.4%, P<.001). The proportion of E. coli in community-acquired bloodstream infections increased in community hospitals only. Community-acquired polymicrobial infections (9.9% vs 5.6%, P<.001) and community-acquired coagulase-negative staphylococci (6.7% vs 3.4%, P<0.001) were more prevalent in university hospitals.CONCLUSIONSThe role of E. coli as predominant pathogen in bloodstream infections has become more pronounced. There are distinct patterns in community and university hospitals, potentially influencing empirical antibiotic treatment.Infect Control Hosp Epidemiol 2016;37:1060–1067

Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

1992 ◽  
Vol 67 (01) ◽  
pp. 111-116 ◽  
Author(s):  
Marcel Levi ◽  
Jan Paul de Boer ◽  
Dorina Roem ◽  
Jan Wouter ten Cate ◽  
C Erik Hack
Keyword(s):  
Monoclonal Antibodies ◽  
Plasminogen Activator ◽  
Plasma Levels ◽  
Fold Increase ◽  
Fibrinolytic System ◽  
Plasminogen Activation ◽  
Plasminogen Activator Activity ◽  
Insight Into

SummaryInfusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Healthcare-Associated Laboratory-Confirmed Bloodstream Infections—Species Diversity and Resistance Mechanisms, a Four-Year Retrospective Laboratory-Based Study in the South of Poland

2021 ◽  
Vol 18 (5) ◽  
pp. 2785
Author(s):  
Agnieszka Chmielarczyk ◽  
Monika Pomorska-Wesołowska ◽  
Dorota Romaniszyn ◽  
Jadwiga Wójkowska-Mach
Keyword(s):  
Bloodstream Infections ◽  
Diagnostic Techniques ◽  
Resistance Mechanisms ◽  
Infection Prevention And Control ◽  
The South ◽  
Coagulase Negative Staphylococci ◽  
Aminoglycoside Resistance ◽  
Gram Negative ◽  
Maldi Tof ◽  
Carbapenem Resistant

Introduction: Regardless of the country, advancements in medical care and infection prevention and control of bloodstream infections (BSIs) are an enormous burden of modern medicine. Objectives: The aim of our study was to describe the epidemiology and drug-resistance of laboratory-confirmed BSI (LC-BSIs) among adult patients of 16 hospitals in the south of Poland. Patients and methods: Data on 4218 LC-BSIs were collected between 2016–2019. The identification of the strains was performed using MALDI-TOF. Resistance mechanisms were investigated according to European Committee on Antimicrobial Susceptibility Testing, EUCAST recommendations. Results: Blood cultures were collected from 8899 patients, and LC-BSIs were confirmed in 47.4%. The prevalence of Gram-positive bacteria was 70.9%, Gram-negative 27.8% and yeast 1.4%. The most frequently isolated genus was Staphylococcus (50% of all LC-BSIs), with a domination of coagulase-negative staphylococci, while Escherichia coli (13.7%) was the most frequent Gram-negative bacterium. Over 4 years, 108 (2.6%) bacteria were isolated only once, including species from the human microbiota as well as environmental and zoonotic microorganisms. The highest methicillin resistant Staphylococcus aureus (MRSA) prevalence was in intensive care units (ICUs) (55.6%) but S. aureus with resistance to macrolides, lincosamides and streptogramins B (MLSB) in surgery was 66.7%. The highest prevalence of E. faecalis with a high-level aminoglycoside resistance (HLAR) mechanism was in ICUs, (84.6%), while E. faecium-HLAR in surgery was 83.3%. All cocci were fully glycopeptide-sensitive. Carbapenem-resistant Gram-negative bacilli were detected only in non-fermentative bacilli group, with prevalence 70% and more. Conclusions: The BSI microbiology in Polish hospitals was similar to those reported in other studies, but the prevalence of MRSA and enterococci-HLAR was higher than expected, as was the prevalence of carbapenem-resistant non-fermentative bacilli. Modern diagnostic techniques, such as MALDI-TOF, guarantee reliable diagnosis.

scholarly journals A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

2021 ◽  
Vol 22 (13) ◽  
pp. 6974
Author(s):  
Omar Taleb ◽  
Mohammed Maammar ◽  
Christian Klein ◽  
Michel Maitre ◽  
Ayikoe Guy Mensah-Nyagan
Keyword(s):  
Dopamine Release ◽  
Intraperitoneal Administration ◽  
Glutamate Transporter ◽  
Fold Increase ◽  
Xanthurenic Acid ◽  
Metabotropic Receptors ◽  
Parent Molecule ◽  
Dopaminergic Activity ◽  
The Brain

Xanthurenic acid (XA) is a metabolite of the kynurenine pathway (KP) synthetized in the brain from dietary or microbial tryptophan that crosses the blood-brain barrier through carrier-mediated transport. XA and kynurenic acid (KYNA) are two structurally related compounds of KP occurring at micromolar concentrations in the CNS and suspected to modulate some pathophysiological mechanisms of neuropsychiatric and/or neurodegenerative diseases. Particularly, various data including XA cerebral distribution (from 1 µM in olfactory bulbs and cerebellum to 0.1–0.4 µM in A9 and A10), its release, and interactions with G protein-dependent XA-receptor, glutamate transporter and metabotropic receptors, strongly support a signaling and/or neuromodulatory role for XA. However, while the parent molecule KYNA is considered as potentially involved in neuropsychiatric disorders because of its inhibitory action on dopamine release in the striatum, the effect of XA on brain dopaminergic activity remains unknown. Here, we demonstrate that acute local/microdialysis-infusions of XA dose-dependently stimulate dopamine release in the rat prefrontal cortex (four-fold increase in the presence of 20 µM XA). This stimulatory effect is blocked by XA-receptor antagonist NCS-486. Interestingly, our results show that the peripheral/intraperitoneal administration of XA, which has been proven to enhance intra-cerebral XA concentrations (about 200% increase after 50 mg/kg XA i.p), also induces a dose-dependent increase of dopamine release in the cortex and striatum. Furthermore, our in vivo electrophysiological studies reveal that the repeated/daily administrations of XA reduce by 43% the number of spontaneously firing dopaminergic neurons in the ventral tegmental area. In the substantia nigra, XA treatment does not change the number of firing neurons. Altogether, our results suggest that XA may contribute together with KYNA to generate a KYNA/XA ratio that may crucially determine the brain normal dopaminergic activity. Imbalance of this ratio may result in dopaminergic dysfunctions related to several brain disorders, including psychotic diseases and drug dependence.

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