Meropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK35 and OmpK36 porins. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor controlling capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae isolate.

Aspergillus niger, the third species responsible for invasive aspergillosis has been considered as a homogeneous species until DNA-based identification uncovered many cryptic species. These species have been recently reclassified into the Aspergillus section Nigri. However little is yet known among the section Nigri about the species distribution and the antifungal susceptibility pattern of each cryptic species. A total of 112 clinical isolates collected from 5 teaching hospitals in France and phenotypically identified as A. niger were analyzed. Identification to the species level was carried out by nucleotide sequence analysis. The Minimum Inhibitory Concentrations (MICs) of itraconazole, voriconazole, posaconazole, isavuconazole and amphotericin B were determined by both the EUCAST and gradient concentration strips methods. Aspergillus tubingensis (n=51, 45.5%) and A. welwitschiae (n=50, 44.6%) were the most common species while A. niger accounted for only 6.3% (n=7). The MICs of azoles drugs were higher for A. tubingensis than for A. welwitschiae. The MIC of amphotericin B was 2 mg/L or less for all isolates. Importantly, MICs determined by EUCAST showed no correlation with those determined by gradient concentration strips methods, these latter being lower than the former (Spearman's rank correlation tests ranging - depending on the antifungal agent - from 0.01 to 0.25; p>0.4). In conclusion, A. niger should be considered as a minority species in the section Nigri. The differences in MICs between species for different azoles underline the importance of accurate identification. Significant divergences in the determination of MIC between EUCAST and gradient concentration strips methods require further investigation.

A case of M. leprae rifampicin resistance after irregular anti-leprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampicin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.

Introduction: This study was performed to evaluate the impacts of vanA-positivity of Enterococcus faecium (EFM) exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study.

Methods: A total of 509 patients with an EFM BSI from eight sentinel hospitals in South Korea during a two-year period were enrolled in this study. Risk factors of the hosts and causative EFM isolates were assessed to determine associations with the 30-day mortality of EFM BSI patients via multivariable logistic regression analyses.

Results: The vanA gene was detected in 35.2% (179/509) of EFM isolates; 131 EFM isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 EFM isolates exhibited atypical phenotypes (group vanA-Atypical), including VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA-positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with an EFM BSI; however, there was no significant difference in the survival rates between the patients of the vanA-VanA and vanA-Atypical groups (log-rank test, P = 0.904).

Conclusions: A high 30-day mortality rate was observed in patients with vanA-positive EFM BSIs, and vanA-positivity of causative EFM was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve clinical outcome of patients with vanA-positive EFM BSI.

Two non-amidated host defence peptides named Pin2[G] and FA1 were evaluated against three types of pathogenic bacteria; two isolated from diabetic foot ulcer patients, Staphylococcus aureus UPD13 and Pseudomonas aeruginosa UPD3, and another from a commercial collection, Salmonella enterica serovar Typhimurium (ATCC 14028). In vitro experiments showed that the antimicrobial performance of the synthetic peptides, Pin2[G] and FA1, was modest, although FA1 was more effective than Pin2[G]. In contrast Pin2[G] had superior in vivo anti-infective activity to FA1 in rabbit wound infections by the diabetic foot ulcer pathogens S. aureus UPD13 and P. aeruginosa UPD3. Indeed, Pin2[G] reduced bacterial colony counts of both S. aureus UPD13 and P. aeruginosa UPD3 by >100,000-fold after 48-72 h on skin wounds of infected rabbits, while in similar infected wounds, FA1 had no major effects at 72-96 h of treatment. Ceftriaxone was equally effective vs. Pseudomonas but less effective vs. S. aureus infections. Additionally, the two peptides were evaluated in mice against intragastrically inoculated S. enterica ser. Typhimurium (ATCC 14028). Only Pin2[G], at 0.56 mg/kg, was effective in reducing systemic (liver) infection by >67-fold, equivalent to the effect of treatment with levofloxacin. Pin2[G] showed superior immunomodulatory activity in increasing chemokine production by a human bronchial cell line and suppressing poly(IC)-induced pro-inflammatory IL6 production. These data showed that the in vitro antimicrobial activity of these peptides was not correlated with their in vivo anti-infective activity, and suggest that other factors such as immunomodulatory activity were more important.

Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on healthcare systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Disease of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The alternative strategy of early use of a β-lactam antibiotics in combination with vancomycin upon initial MRSA bacteremia detection has shown promise. While this concept has gained international attention, providers should give this strategy serious consideration prior to implementation. The objective of this review is to examine retrospective and prospective evidence for early combination with vancomycin and β-lactam antibiotics, as well as explore potential consequences of combination therapy.

Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001). We previously reported the broad-spectrum activity of manogepix but also observed a correlation between increased manogepix and fluconazole MICs. Here we extended this study and included isolates with acquired fluconazole resistance.

Isolates (n=835) were identified using CHROMagar, MALDI-TOF and, when needed, ITS-sequencing. EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole and voriconazole. Manogepix wildtype-upper-limit (WT-UL) values were established following EUCAST-principles for ECOFF setting allowing wildtype/non-wildtype classification. Drug-specific MIC correlations were investigated using Pearson's correlation.

Manogepix modal MICs were low (range 0.004-0.06 mg/L against 16/20 included species). Exceptions were C. krusei and C. inconspicua, and to a lesser extent C. kefyr and Pichia kluyveri. The activity was independent of Fks echinocandin hot-spot alterations (n=17). Adopting the WT-UL established for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis, 14/724 (1.9%) isolates were non-wildtype for manogepix. Twelve of these (85.7%) were also non-wildtype for fluconazole. A statistically significant correlation was observed between manogepix and fluconazole MICs for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis (Pearson r=0.401-0.575), but not between manogepix and micafungin or amphotericin B MICs for any species except C. tropicalis (r=0.519 for manogepix versus micafungin).

Broad-spectrum activity was confirmed for manogepix against contemporary yeast. However, a 1-4 two-fold-dilution increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted.

Linezolid has strong antimicrobial activity against the multidrug-resistant (MDR) strains of Mycobacterium tuberculosis. Little is known about the distribution of linezolid in tuberculosis (TB) lesions in patients with MDR-TB. The aim of this study is to evaluate the distribution of linezolid in TB lesions in patients with spinal MDR-TB. Nine patients with spinal MDR-TB were enrolled prospectively from August 2019 to February 2020. The patients received a linezolid-containing anti-TB treatment regimen and needed surgery for the removal of TB lesions. During the operation, nine blood samples, eight diseased bone tissue samples, seven pus samples and four granulation tissue samples were collected simultaneously and 2 h after the oral administration of 600 mg of linezolid. Linezolid concentrations in plasma, diseased bone tissue, pus, and granulation tissue samples were subjected to high-performance liquid chromatography–tandem mass spectrometry. At sample collection, the mean concentrations of linezolid in plasma, diseased bone tissue, pus, and granulation tissue samples of the nine patients were 11.14 ± 5.82, 5.94 ± 4.27, 11.09 ± 4.58, 14.08 ± 10.61 mg/L, respectively. The mean ratios of linezolid concentration in diseased bone/plasma, pus/plasma, and granulation/plasma were 53.84%, 91.69%, and 103.57%, respectively. The mean ratios of linezolid concentration in pus/plasma and granulation/plasma were higher than those in diseased bone/plasma, and the difference was statistically significant (t =-2.810, p = 0.015; t =-4.901, p = 0.001). In conclusion, linezolid had different concentration distributions in different types of TB infected tissues in patients with spinal MDR-TB.

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MIC_{ciprofloxacin} 0.25 mg/L, MIC_meropenem 2 mg/L) and CW44 (MIC_{ciprofloxacin} 0.5 mg/L, MIC_meropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log₁₀ CFU/mL) and biofilm (>8log₁₀ CFU/cm²) bacteria at 120h (MIC_{ciprofloxacin} up to 8 mg/L, MIC_meropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log₁₀ CFU/mL and ≤6log₁₀ CFU/cm² at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

Background

Optimal concentrations of unbound antimicrobials are essential for maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model.

Methods

Design

Prospective, three phase intervention observational study.

Subjects

Healthy Merino sheep.

Interventions

Eight sheep were subject to three experimental phases; normoalbuminemia, hypoalbuminemia using plasmapheresis and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone 40 mg/kg and ertapenem 15 mg/kg were given intravenously. Blood samples were collected at pre-defined intervals and analyzed using an ultra-high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters such as area under the curve (AUC_0-24), plasma clearance (CL) and apparent volume of distribution in the terminal phase (V_d) were estimated and compared between the phases.

Results

The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC_0-24 and higher CL of total and unbound concentrations of ceftriaxone compared to the other phases. Whereas albumin replacement led to higher AUC_0-24 and lower CL compared to other phases for both drugs. The V_d for total drug concentrations for both drugs were significantly lower with albumin replacement.

Conclusions

For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

Security researchers are demonstrating how you can use the Windows 10 flaw, CVE-2020-0601, to spoof the trusted digital certificates for official website domains on Google's Chrome browser. These same certificates can warn you about hacking attempts.

The FBI seizes the internet domain to WeLeakInfo.com, a site that was cataloging billions of records, such as email addresses and passwords, from more than 10,300 data breaches at various companies and service providers.

The password-fatigued masses will be pleased to find Keeper's new 30 percent off deal, which brings it down to $20.99 per year from its typical $29.99.

'As CEO of Avast, I feel personally responsible and I would like to apologize to all concerned,' wrote Ondrej Vlcek following a PCMag-Motherboard investigation into the privacy risks around the data harvesting.

The hackers have been using files and emails that warn about a new coronavirus strain to trick users into opening them. Doing so can secretly deliver malware to the victim's machine.

Google's Takeout service was designed to let people download their data, but accidentally sent videos from Google Photos accounts to strangers.

Watch out for suspicious interview requests. 'The main focus of this phishing campaign was stealing email account information of the victims, and finding information about their contacts/networks,' the cybersecurity experts at Certfa Lab warned on Wednesday.

Malware on an air-gapped computer can transmit data like Morse code by changing screen brightness in a way that's invisible to the naked eye but easily recorded with a camera.

Parenting styles run the gamut and so do the features in parental control and monitoring utilities. We've tested the top hardware- and software-based services to help you choose the right one for your family.

The JSE fell on Tuesday as global markets tumbled on the back of a rout in crude oil prices.

"The entire energy market is still on a knife edge," says an economist.

The local bourse inched higher on Wednesday as global stocks took a breather following consecutive sessions of weakness.

Local stocks advanced for a second consecutive session on Thursday as global markets remained resurgent.

The surge in stocks was on the back of positive news from trials being conducted on a potential treatment for the coronavirus. With most economies looking to partially reopen their economies, this brought a jump across most asset classes including commodities.

Stock markets plunged on Thursday after economic growth data confirmed fears of Covid-19's bruising impact on the world economy.

Deep losses were recorded across most European benchmarks except the FTSE 100 which managed to trade relatively flat on the day.

Oil was headed for the longest run of daily gains in more than nine months on signs the worst of the supply glut may be over as production cuts start to take effect.

On the currency market, the rand traded softer against the greenback as it slipped to a session low of R18.77/$.

Still, there was disappointment in terms of economic data following the release of the SACCI Business Confidence index data for April which came in at 77.8, compared to a forecast of 89.2.

Oil headed for its first back-to-back weekly gain since February as output cuts from the biggest producers and a nascent recovery in demand began to rebalance a market awash with crude.

A new paper sketches out the landscape and tensions in civic education as philanthropies look for ways to support the field.

In number 10 in our countdown, I tried to offer a few thoughts to funders as they embraced new agendas and looked to avoid repeating yesterday's missteps.

Around the world, education is the largest recipient of philanthropic giving by a large margin, but in the United States, funders are moving away from investing in K-12 schools in favor of early childhood and higher education.

"Folks in some foundations are quietly expressing frustration that they've been cautioned to stay in their lane and only fund things aligned with their pre-COVID strategy," says Stacey Childress.

BACKGROUND AND OBJECTIVES:

Antibiotic therapy is often prescribed for suspected community-acquired pneumonia (CAP) in children despite a lack of knowledge of causative pathogen. Our objective in this study was to investigate the association between antibiotic prescription and treatment failure in children with suspected CAP who are discharged from the hospital emergency department (ED).

BACKGROUND:

Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo.

BACKGROUND:

Mexican-origin women breastfeed at similar rates as white women in the United States, yet they usually breastfeed for less time. In our study, we seek to identify differences in Mexican-origin women’s breastfeeding intentions, initiation, continuation, and supplementation across nativity and country-of-education groups.

BACKGROUND AND OBJECTIVES:

Runaway youth and homeless youth are at risk for adverse mental health outcomes. These 2 populations are frequently pooled together in both research and interventions yet may have unique health needs. We sought to assess differences in mental health outcomes among these populations.

BACKGROUND AND OBJECTIVES:

Children with medical complexity (CMC) comprise only 6% of the pediatric population, account for ~40% of pediatric health care spending, and provide an important opportunity for cost saving. Savings in this group can have an important impact on pediatric health care costs. The objective of this study was to assess the impact of a multicenter care management program on spending and use in CMC.

BACKGROUND AND OBJECTIVES:

Rates of sexually transmitted infections (STIs) have increased over the decade. Guidelines recommend HIV testing with incident STIs. Prevalence and factors associated with HIV testing in acute STIs are unknown in adolescents. Our objective was to determine the prevalence of completed HIV testing among adolescents with incident STIs and identify patient and health care factors associated with HIV testing.

BACKGROUND:

Pediatricians are less frequently sued than other physicians. When suits are successful, however, the average payout is higher. Little is known about changes in the risk of litigation over time. We sought to characterize malpractice lawsuit trends for pediatricians over time.

BACKGROUND AND OBJECTIVES:

The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. We hypothesized that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations.

WRS Health is an innovative and clinician-centered solution that improves charting accuracy, individualizes patient-care plans, and enhances reimbursements. This application is definitely a top contender in the electronic medical record (EMR) field.

Wix Stores has a smooth offering that's strongly geared toward beginners who just want to get off the ground quickly. More advanced users or those who need more in-depth customizability, however, will need to look elsewhere.

Web Hosting Hub offers excellent customer support and strong shared and WordPress hosting, but it lacks the advanced hosting options that many growing businesses will eventually need.

The Whistle GO Explore pet tracker improves on the previous generation in nearly every while, while adding a few new tricks in the process.

HostGator is an excellent web hosting service that's simple to use and offers an array of useful plans for consumers and small businesses. It's our top pick for shared web hosting and for novice webmasters in general.

With the UEFA Champions League resuming next week, UEFA.com looks at which players have been hitting the heights on the domestic front.

UEFA.com studies the statistics to find out which players are predicted for big Matchday 7 totals.

Erling Braut Haaland and Robert Lewandowski continued to hit the net, although injury means the latter is likely to miss the second leg.