Weinreichbro2035

Currently used PAM therapeutics inhibited N. fowleri replication and EdU incorporation in vitro. EdA (7-deaza-2'-deoxy-7-ethynyladenosine), an adenine analog, also was incorporated by N. fowleri but was more cytotoxic than EdU. In summary, EdU incorporation could be used as a complimentary method for drug discovery for these neglected pathogens.Discordant results between genotypic drug susceptibility testing (gDST) and phenotypic DST (pDST) for Mycobacterium tuberculosis isolates with disputed (discordance between gDST and pDST results) mutations affect rifampin (RIF)-resistant (RR) and multidrug-resistant (MDR) tuberculosis (TB) treatments due to a lack of practical clinical guidelines. To investigate the role of disputed rpoB mutations in M. tuberculosis and TB treatment outcomes, initial isolates of 837 clinical RR- or MDR-TB cases confirmed during 2014 to 2018 were retested using agar-based RIF pDST and rpoB gene sequencing. MICs were determined for isolates with disputed rpoB mutations. Disputed rpoB mutations were identified in 77 (9.2%) M. tuberculosis isolates, including 50 (64.9%) and 14 (18.2%) phenotypically RIF- and rifabutin (RFB)-resistant isolates, respectively. The predominant single mutations were those encoding L533P (a change of L to P at position 533) (44.2%) and L511P (20.8%). Most of the isolates harboring mutations encoding L511P (87.5%), H526N (100%), D516Y (70.0%), and L533P (63.6%) had MICs of ≤1 mg/liter, whereas isolates harboring the mutation encoding H526L (75%) had a MIC of >1 mg/liter. Of the 63 cases with treatment outcomes available, 11 (17.5%) cases died, 1 (1.6%) case transferred out, and 51 (81%) cases had favorable outcomes, including 8 and 20 cases treated with standard-dose RIF- and RFB-containing regimens, respectively. Excluding cases that transferred out or received no or 1-day treatment, we observed statistically significant differences between the outcomes using active and inactive fluoroquinolones (FQs) (P = 0.008, odds ratio = 0.05 [95% confidence interval, 0.01 to 0.38]) in 57 cases (where active means a case susceptible to the drug and inactive means a case resistant to the drug or drug not used). We concluded that disputed rpoB mutations are not rare. Depending on the resources available, sequencing and/or MIC testing is recommended for better management of RR- and MDR-TB cases.The objective of this study was to describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included. Total micafungin plasma and peritoneal fluid were subjected to a population pharmacokinetic analysis using Pmetrics. Monte Carlo simulations were performed considering the total area under the curve from 0 to 24 h (AUC0-24)/MIC ratios in plasma. Micafungin concentrations in both plasma and the peritoneal exudate were best described by a three-compartmental PK model with the fat-free mass (FFM) as a covariate of clearance (CL) and the volume of the central compartment (Vc). The mean parameter estimates (standard deviations [SD]) were 1.18 (0.40) liters/h for CL and 12.85 (4.78) liters for Vc. The mean peritoneal exudate/plasma ratios (SD) of micafungin were 25% (5%) on day 1 and 40% (8%) between days 3 and 5. Dosing simulations supported the use of standard 100-mg daily dosing for Candida albicans (FFM, less then 60 kg), C. glabrata (FFM, less then 50 kg), and C. tropicalis (FFM, less then 30 kg) on the second day of therapy. There is a moderate penetration of micafungin into the peritoneal cavity (25 to 40%). For empirical treatment, a dose escalation of at least a loading dose of 150 mg depending on the FFM of patients and the Candida species is suggested to be effective from the first day of therapy.The Qnr pentapeptide repeat proteins interact with DNA gyrase and protect it from quinolone inhibition. see more The two external loops, particularly the larger loop B, of Qnr proteins are essential for quinolone protection of DNA gyrase. The specific QnrB1 interaction sites on DNA gyrase are not known. In this study, we investigated the interaction between GyrA and QnrB1 using site-specific photo-cross-linking of QnrB1 loop B combined with mass spectrometry. We found that amino acid residues 286 to 298 on the tower domain of GyrA interact with QnrB1 and play a key role in QnrB1 protection of gyrase from quinolone inhibition. Alanine replacement of arginine at residue 293 and a small deletion of amino acids 286 to 289 of GyrA resulted in a decrease in the QnrB1-mediated increase in quinolone MICs and also abolished the QnrB1 protection of purified DNA gyrase from ciprofloxacin inhibition.Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/ml, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg treatment group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data show that AmBisome has significant antifungal activity against C. auris infection in vitro and in vivo.Outpatient parenteral antimicrobial therapy (OPAT) is a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting; however, data are limited describing the use and safety of liposomal amphotericin B (L-AMB). Records of patients receiving L-AMB OPAT between 1/1/2015 and 7/31/2018 were retrospectively reviewed. The primary objective was to describe the OPAT patient population discharged on L-AMB and evaluate factors associated with readmission and adverse events (AEs). Analysis was performed to evaluate for predictors of worse outcomes. Forty-two patients (67% male, median age 50 years) were identified, most of whom were treated for histoplasmosis. The most common doses of L-AMB were 3 mg/kg (n = 16, 38%) or 5 mg/kg (n = 14, 33%) based on actual body weight. Twenty-six (62%) patients completed their anticipated course of L-AMB. Twenty-two (52%) patients were readmitted within 30 days of discharge; median time to readmission was 11 days (interquartile range [IQR] 5 to 18). While hypokalemia and acute kidney injury (AKI) were common, occurring in 26 (62%) and 20 (48%) patients, respectively, only 5 (12%) were readmitted to the hospital due to L-AMB-associated AEs. Ninety percent of patients achieved at least partial renal recovery within 30 days after L-AMB discontinuation. Factors significantly associated with AKI include higher L-AMB dose, lower serum potassium levels after therapy initiation, and receipt of potassium supplementation at discharge. L-AMB is associated with significant AEs; however, these results suggest that treatment is feasible in the outpatient setting with close monitoring, as the majority of AEs were managed effectively in an outpatient without long-term sequelae.Current growth-based antibiotic susceptibility testing (AST) is too slow to guide early therapy. We previously developed a diagnostic approach that quantifies antibiotic-induced transcriptional signatures to distinguish susceptible from resistant isolates, providing phenotypic AST 24 to 36 h faster than current methods. Here, we show that 10 transcripts optimized for AST of one fluoroquinolone, aminoglycoside, or beta-lactam reflect susceptibility when the organism is exposed to other members of that class. This finding will streamline development and implementation of this strategy, facilitating efficient antibiotic deployment.

To ask all clinical, administrative and support staff affiliated with a large network of healthcare facilities to identify the conditions that they consider as non-negotiable for their own deaths to be regarded as good.

All 3495 staff of a healthcare network were asked to rank 10 conditions according to how non-negotiable they would be for themselves during their final 3 months or few hours for their own deaths to be considered as good. They were also asked about whether they had thought about their own death in the last 3 months, if they had a will, believed in God, and in the possibility of a good death, and the intensity of their fear of death.

2971 (85%) completed the survey. Most were female (79%) and clinical staff (65%). 93% believed in God, 60% had thought about their death recently, 33% had an intense fear of death, and 4% had a will. 64% considered a good death possible. Participants ranked dying at a preferred place, emotional support from family and friends and relief from physical symptoms as their top priorities. The lowest ranked conditions were (from the bottom) relief from psychological distress, performance of rituals and the right to terminate life. There were no statistically significant differences across genders or individual occupational groups.

Most of conditions for a good death of interest to healthcare professionals could be provided without sophisticated medical infrastructure or specialised knowledge, opening the door for new support services to make it possible for everyone, anywhere.

Most of conditions for a good death of interest to healthcare professionals could be provided without sophisticated medical infrastructure or specialised knowledge, opening the door for new support services to make it possible for everyone, anywhere.

To compare cancer centre (CC) executives' attitudes towards palliative care between National Cancer Institute-designated CCs (NCI-CCs) and non-NCI-designated CCs (non-NCI-CCs) in 2018 and to examine the changes in attitudes and beliefs between 2009 and 2018.

CC chief executives at all NCI-CCs and a random sample of non-NCI-CCs were surveyed from April to August 2018. Twelve questions examined the executives' attitudes towards palliative care integration, perceived barriers and self-assessments. The primary outcome was agreement on the statement 'a stronger integration of palliative care services into oncology practice will benefit patients at my institution.' Survey findings from 2018 were compared with data from 2009 to examine changes in attitudes.

52 of 77 (68%) NCI-CCs and 88 of 126 (70%) non-NCI-CCs responded to the survey. A vast majority of executives at NCI-CCs and non-NCI-CCs endorsed palliative care integration (89.7% vs 90.0%; p>0.999). NCI-CCs were more likely to endorse increasing funding for palliative care (52.5% vs 23.1%; p=0.01) and hiring physician specialists (70.0% vs 37.5%; p=0.004) than non-NCI-CCs. The top three perceived barriers among NCI-CCs and non-NCI-CCs were limited institutional budgets (57.9% vs 59.0%; p=0.92), poor reimbursements (55.3% vs 43.6%; p=0.31), and lack of adequately trained palliative care physicians and nurses (52.6% vs 43.6%; p=0.43). Both NCI-CCs and non-NCI-CCs favourably rated their palliative care services (89.7% vs 71.8%; p=0.04) with no major changes since 2009.

CC executives endorse integration of palliative care, with greater willingness to invest in palliative care among NCI-CCs. Resource limitation continues to be a major barrier.

CC executives endorse integration of palliative care, with greater willingness to invest in palliative care among NCI-CCs. Resource limitation continues to be a major barrier.