Durlobactam (DUR, also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem/cilastatin (IMI/CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In Part A, subjects including an elderly cohort (DUR 1 g) received single ascending doses of DUR 0.25-8 g. In Part B, multiple ascending dose of DUR 0.25-2 g were administered every 6 hours (q6h) for 29 doses. In Parts C and D, the drug-drug interaction (DDI) potential, including safety, of DUR (1 g) with SUL (1 g) and/or IMI/CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI/CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated either alone or in combination with SUL and/or IMI/CIL. After single and multiple doses, DUR demonstrated linear dose proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug:drug interaction potential was identified between DUR and SUL and/or IMI/CIL. SUL-DUR, 1 g (of each component) administered q6h with a 3 hour IV infusion, is under development for the treatment of serious infections due to A. baumannii.

The SHV β-lactamases (BLs) have undergone strong allele diversification that changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted five positions as relevant for the β-lactamase inhibitor (BLI) resistant (2br) phenotype, 12 as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and two positions were related to solely the narrow spectrum (2b) phenotype. These positions and additional 6 positions described in other studies (including one promoter mutation), were systematically substituted and investigated for their substrate specificities in a BL-free E. coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of the positions 238 and 179 for the 2be phenotype and 69 for the 2br phenotype. The substitutions E240K and E240R, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI-resistance potential of these substitutions. The substitutions M129V, A234G, S271I and R292Q conferred latent resistance to cefotaxime. In addition, 7 positions that were found to be not always associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to a A146V mutant with the 2b phenotype resulted in a highly increased resistance to BLIs, cefepime and ceftaroline but not to 3^rd generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin/tazobactam or cefepime to treat different infectious diseases caused by gram-negatives.

A total of 2,283 Salmonella spp. isolates were recovered from 18,334 samples including patients with diarrhea, food of animal origin and pets across 5 provinces of China. The highest prevalence of Salmonella spp. was detected in chicken meats (39.3%, 486/1,237). Fifteen serogroups and 66 serovars were identified, with Typhimurium and Enteritidis being the most dominant. Most (85.5%, 1,952/2,283) isolates exhibited resistant to ≥ 1 antimicrobial and 56.4% were multi-drug resistant (MDR). A total of 222 isolates harbored extended-spectrum β-lactamases (ESBLs), 200 of which were CTX-M-type that were mostly detected from chicken meat and turtle fecal. Overall, eight bla_CTX-M genes were identified, with bla_CTX-M-65, bla_CTX-M-123, bla_CTX-M-14, bla_CTX-M-79, and bla_CTX-M-130 being the most prevalent. Totally, 166 of the 222 ESBL-producing isolates had amino acid substitutions in GyrA (S83Y, S83F, D87G, D87N, and D87Y) and ParC (and S80I), whilst the PMQR-encoding genes oqxA/B, qepA, and qnrB/S were detected in almost all isolates. Of the fifteen sequence types (STs) identified in the 222 ESBLs, ST17, ST11, ST34, and ST26 ranked among the top 5 in the number of isolates. Our study revealed considerable serovars diversity, high prevalence of co-occurrence of MDR determinants, including CTX-M-type ESBLs, QRDRs mutations and PMQR genes. This is the first report of CTX-M-130 Salmonella spp. from patients with diarrhea and QRDRs mutations from turtle fecal samples. Our study emphasizes the importance of actions, both in the health care settings and in the veterinary medicine sector, to control the dissemination of MDR, especially the CTX-M Salmonella spp. isolates.

The stunning allegation reportedly comes from a forensic analysis Amazon CEO Jeff Bezos commissioned to determine the culprit behind the hack, which resulted in his private photos ending up in the hands of the National Enquirer.

The big difference between Spotify and Amazon Music Unlimited is Amazon offers an affordable tier of service available on just one Echo device. Here's how else they differ.

Amazon Fire is more than just an e-reader. Download some of the best apps from Amazon's Appstore to have fun, be productive, and get more organized.

Right now you can grab an Amazon Echo Dot two-speaker bundle for just $50. Plus, the 55-inch Vizio M-Series Quantum 4K Smart TV and Anker charging accessories are on sale.

You don't have to fork over a bunch of cash to get a bunch of storage. PNY flash drives, SD cards, and portable drives are on sale at Amazon, with prices starting as low as $5.84.

On the tech front, expect deals on Alexa smart speakers and displays, Fire TV media streamers, Fire tablets, Kindle ebook readers, home security devices, TVs, gaming gear, printers, and more.

Senior Steven Shalamanda began his education at Penn State Schuylkill knowing he was interested in becoming an optometrist. But it was this high-achieving biology student’s internship with a local practice that affirmed his vision for the future. In fall 2020, Shalamanda will begin his doctor of optometry program at the Pennsylvania College of Optometry.

Starting at $249.99, it's pricey, but the previous generation is a PCMag Editors' Choice product, and this new model promises to be even better.

The latest low-cost Kindle improves night reading with its front light, but the slightly more expensive Paperwhite offers better overall value for most readers.

The waterproof Kindle Paperwhite offers more for your money than any other ebook reader on the market.

Which Amazon Kindle should you buy? Whether you're new to ereaders in general or are looking to upgrade, we have the details on what each Kindle brings to the table.

The 2019 edition of the slim, waterproof Amazon Kindle Oasis adds a warmth-adjustable backlight for less eye strain, thought most people will be just fine spending nearly half the price on the Paperwhite.

Matchbook allowed cheap Kindle editions to be offered with a print book purchase.

No matter your age, the Amazon Kindle Kids Edition is a terrific value for anyone looking to buy an ebook reader.

With plenty of best sellers at $4.99 or less, like Midnight in Chernobyl, you're basically getting a free book or two.

The top-rated Kindle Paperwhite, a PCMag Editors' Choice product, is available right now from $84.99 ($45 off) and the new Kindle is on sale starting at $59.99 ($30 off).

In India and China, indigenous drug manufacturers market arbitrarily combined parenteral β-lactam and β-lactamase inhibitors (BL-BLIs). In these fixed-dose combinations, sulbactam or tazobactam is indiscriminately combined with parenteral cephalosporins, with BLI doses kept in ratios similar to those for the approved BL-BLIs. Such combinations have been introduced into clinical practice without mandatory drug development studies involving pharmacokinetic/pharmacodynamic, safety, and efficacy assessments being undertaken. Such unorthodox combinations compromise clinical outcomes and also potentially contribute to resistance development.

Right now you can save $10 when you buy two Echo Flex mini smart speakers and use the promo code below at checkout.

You can tap into a variety of podcasts on your Amazon Echo via Apple Podcasts, Spotify, iHeartRadio, and TuneIn. Here's how.

Right now the popular Echo Dot is $20 off and Echo Buds are $40 off. Plus, you can save up to $35 on the Kindle and Kindle Paperwhite, and up to $40 on the Echo Show 5 or 8.

Mathematics Vision Project has dismissed the lawsuit after the surprising move the company made this summer to take legal action against one of its most vocal parent critics.

A tweet from the former president about education's role in addressing inequality and lack of opportunities drew split reactions and a chance to review his record and where K-12 stands in the political sphere.

Here's a breakdown of Amazon's revenue from across its e-commerce and retail ecosystem, cloud infrastructure, streaming services, consumer devices, advertising business, and beyond.

Holders Barcelona, fellow two-time winners Chelsea, Porto and debutants Hoffenheim won their quarter-finals to reach Nyon.

With Ramaphosa sworn in as president, the SA public will be watching closely to see if, and when, he reshuffles Jacob Zuma's last Cabinet.

Bloomberg says People's Liberation Army operatives added tiny, nefarious microchips to server motherboards made by Super Micro and used by Apple and Amazon, among others. All three companies pushed back hard on the story.

DOVER, Del. – Governor John Carney hosted 30 guests Wednesday evening at a Ramadan Iftar dinner at Woodburn, including members of Delaware’s Muslim community and statewide elected officials. The Iftar is the evening meal after sunset that concludes the daily fasting during the month of Ramadan, which ends the evening of June 24 this year. […]

It's called the Echo Input Portable Smart Speaker Edition and offers up to 11 hours of use on a single charge.

The project, which includes companies such as Philips Hue manufacturer Signify, Ikea, and Samsung SmartThings, will help ensure that smart home products work across platforms with the three voice assistants, Amazon's Alexa, Apple's Siri, and Google's Assistant.

Apple AirPods are set to get some new competition from Amazon, and I'd bet money on Alexa Earbuds being significantly cheaper than Apple's offering.

Internal documents reveal Amazon sees this as a health and wellness product that's voice-activated and controlled via a smartphone app.

Participants of a short-term outreach event in July demonstrated God's love and plan for salvation with people in Manaus, the capital of the Amazonas State.

OM Chile celebrates Christmas with the boys and girls of two children's homes in Santiago.

Yamaha Motor India Group (YMIG) on Saturday announced that its employees have joined the fight against the novel Coronavirus Pandemic by voluntarily donating a day's salary from the April month. The...

By Devika Singh The country's oldest music label company is singing a different tune. From podcasts to a dedicated film production unit, Saregama is looking beyond music licensing to broaden its appeal. Vikram Mehra talks to Devika Singh about creating and monetising IPs, why the company will not launch a streaming app, and more. Saregama […]

Will partnerships such as these be the norm in the digital entertainment market in India?

Apps like Instagram are largely reaching the first 150-200 million users. We are going after mass market users who consume content in regional languages.

This is to create, produce and distribute content via the Microsoft Azure cloud platform.

The Myntra Extended Network Through Store Activation (MENSA), a kirana model, allows local business owners to earn by assisting in deliveries.

Ujjwal Chaudhry, director, RedSeer Consulting, says, “Metro consumers buy more branded products, but the same value proposition would not be as attractive to a tier II consumer.”

A grenade attack was launched in Jammu and Kashmir's Srinagar. The attack led to the death of a man from Saharanpur. On the other hand, 20 people were injured. These were taken to nearest hospital where two of them were told to be seriously injured<br />The attack was done

Rohit Sharma shared a picture of daughter Samaira surrounded by her toys.

INR-USD future contracts will be available for 22 hours across all time zones for all global participants from GIFT IFSC.

This Ramadan, try this incredibly delicious paratha recipe for iftar that will leave you drooling for more.

"The first season was one of the top 3 most-watched Amazon Original Series from India in 2019," said Aparna Purohit, Head of Amazon Originals

"Agneepath was made years before.. how did this happen," wrote Big B