Toward the detection of the triatomic negative ion SPN−: Spectroscopy and potential energy surfaces

High level theoretical calculations using coupled-cluster theory were performed to provide an accurate description of the electronic structure, spectroscopic properties, and stability of the triatomic negative ion comprising S, N, and P. The adiabatic electron affinities (AEAs) and vertical detachment energies (VDEs) of PNS, SPN, PSN, and cyc-PSN were calculated. The predicted AEA and VDE of the linear SPN isomer are large: 2.24 and 3.04 eV, respectively. The potential energy surfaces (PESs) of the lowest-lying electronic states of the SPN isomer along the PN and SP bond lengths and bond angle were mapped. A set of spectroscopic parameters for SPN, PNS, and PSN in their electronic ground states is obtained from the 3D PESs to help detect these species in the gas phase. The electronic excited state SPN (12A”) is predicted to be stable with a long lifetime calculated to be 189.7 µs. The formation of SPN in its electronic ground state through the bimolecular collision between S + PN and N + PS is also discussed

Effect of epiretinal electrical stimulation on the glial cells in a rabbit retinal eyecup model

IntroductionWe examined how pulse train electrical stimulation of the inner surface of the rabbit retina effected the resident glial cells. We used a rabbit retinal eyecup preparation model, transparent stimulus electrodes, and optical coherence tomography (OCT). The endfeet of Müller glia processes line the inner limiting membrane (ILM).MethodsTo examine how epiretinal electrode stimulation affected the Müller glia, we labeled them post stimulation using antibodies against soluble glutamine synthetase (GS). After 5 min 50 Hz pulse train stimulation 30 μm from the surface, the retina was fixed, immunostained for Müller glia, and examined using confocal microscopic reconstruction. Stimulus pulse charge densities between 133–749 μC/cm2/ph were examined.ResultsHigh charge density stimulation (442–749 μC/cm2/ph) caused significant losses in the GS immunofluorescence of the Müller glia endfeet under the electrode. This loss of immunofluorescence was correlated with stimuli causing ILM detachment when measured using OCT. Müller cells show potassium conductances at rest that are blocked by barium ions. Using 30 msec 20 μA stimulus current pulses across the eyecup, the change in transretinal resistance was examined by adding barium to the Ringer. Barium caused little change in the transretinal resistance, suggesting under low charge density stimulus pulse conditions, the Müller cell radial conductance pathway for these stimulus currents was small. To examine how epiretinal electrode stimulation affected the microglia, we used lectin staining 0–4 h post stimulation. After stimulation at high charge densities 749 μC/cm2/ph, the microglia under the electrode appeared rounded, while the local microglia outside the electrode responded to the stimulated retina by process orientation inwards in a ring by 30 min post stimulation.DiscussionOur study of glial cells in a rabbit eyecup model using transparent electrode imaging suggests that epiretinal electrical stimulation at high pulse charge densities, can injure the Müller and microglia cells lining the inner retinal surface in addition to ganglion cells

Sialidase Inhibitors with Different Mechanisms

Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for under-standing sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors

Stratification of the Impact of Inappropriate Empirical Antimicrobial Therapy for Gram-Negative Bloodstream Infections by Predicted Prognosis

The bloodstream infection mortality risk score (BSIMRS) predicts the outcome of patients with Gram-negative bloodstream infections (BSI) with high discrimination. This retrospective cohort study examined the impact of inappropriate antimicrobial therapy on mortality in adult patients with Gram-negative BSI admitted to Palmetto Health Hospitals in Columbia, SC, USA, from 1 January 2011 to 31 December 2012 after stratification by predicted prognosis at initial presentation using BSIMRS. A multivariate Cox regression model was used to identify independent risk factors for 28-day mortality overall and within each predefined BSIMRS category (\u3c5, 5 to 9, and ≥10). Relative risk reduction (RRR), absolute risk reduction (ARR), and number needed to treat (NNT) were calculated from a predictive logistic regression model of mortality. Overall, 390 unique patients with first episodes of Gram-negative BSI were identified. The median age was 66 years, and 229 (59%) were women. There was significant association between inappropriate antimicrobial therapy and mortality in patients with BSIMRS of 5 to 9 (adjusted hazard ratio [aHR], 3.55; 95% confidence intervals [CI], 1.22 to 8.31; P = 0.02) and BSIMRS of ≥10 (aHR, 4.99; 95% CI, 1.09 to 22.87; P = 0.04) but not in those with BSIMRS of \u3c5 (aHR, 3.34; 95% CI, 0.17 to 22.77; P = 0.34). RRR, ARR, and NNT were 0.25, 0.02, and 63 for BSIMRS of \u3c5; 0.56, 0.32, and 3 for BSIMRS of 5 to 9; and 0.39, 0.39, and 3 for BSIMRS of ≥10, respectively. There is a significant benefit from appropriate antimicrobial therapy in patients with Gram-negative BSI with guarded (BSIMRS of 5 to 9) and poor (BSIMRS of ≥10) predicted prognosis. Survival difference remains unclear among those with good predicted prognosis (BSIMRS of \u3c5) at initial presentation

Application of Fluoroquinolone Resistance Score in Management of Complicated Urinary Tract Infections

The fluoroquinolone resistance score (FQRS) predicts the probability of fluoroquinolone resistance with good discrimination. The score has been derived from patients with bloodstream infections caused by Gram-negative bacteria and is based on fluoroquinolone use within the past 6 months, among other clinical and health care exposure criteria. This study aims to examine the utility of the FQRS in patients with complicated urinary tract infections (cUTI) and determine whether extension of prior fluoroquinolone use to 12 months improves model discrimination. Adults with cUTI at Palmetto Health in central South Carolina, USA, from 1 April 2015 through 31 July 2015 were prospectively identified. Multivariate logistic regression was used to examine the association between prior fluoroquinolone use and resistance. Among 238 patients, 54 (23%) had cUTI due to fluoroquinolone-resistant bacteria. Overall, the median age was 66 years, 162 (68%) patients were women, and 137 (58%) patients had cUTI due to Prior exposure to fluoroquinolones within 3 months (adjusted odds ratio [aOR], 23.4; 95% confidence interval [CI], 8.2 to 76.8; \u3c 0.001) and within 3 to 12 months (aOR, 13.2; 95% CI, 3.1 to 68.4; \u3c 0.001) was independently associated with fluoroquinolone resistance compared to no prior use. The area under the receiver operating characteristic curve for the FQRS increased from 0.73 to 0.80 when prior fluoroquinolone use was extended from 6 to 12 months. FQRSs of ≥2 and ≥3 had negative predictive values of 91% and 90%, respectively. The modified FQRS stratifies patients with cUTI on the basis of the predicted probability of fluoroquinolone resistance with very good discrimination. Application of the modified FQRS may improve antimicrobial utilization in patients with acute pyelonephritis

Impact of Follow up Blood Cultures on Outcomes of Patients with Community-Onset Gram-Negative Bloodstream Infection

Background: The role of follow up blood cultures (FUBC) in the management of gram-negative bloodstream infection (GN-BSI) remains controversial. This retrospective cohort study examines the association between obtaining FUBC and mortality in GN-BSI. Methods: Hospitalized adults with community-onset GN-BSI at Prisma Health-Midlands hospitals in South Carolina, USA from January 1, 2010 to June 30, 2015 were identified. Patients who died or were discharged from hospital within 72 h were excluded to minimize impact of survival and selection biases on results, respectively. Multivariate Cox proportional hazards regression was used to examine association between obtaining FUBC and 28-day all-cause mortality after adjustment for the propensity to obtain FUBC. Findings: Among 766 patients with GN-BSI, 219 (28.6%) had FUBC obtained and 15 of 219 (6.8%) FUBC were persistently positive. Overall, median age was 67 years, 438 (57%) were women, 457 (60%) had urinary source of infection, and 426 (56%) had BSI due to . Mortality was significantly lower in patients who had FUBC obtained than in those who did not have FUBC (6.3% vs. 11.7%, log-rank = 0.03). Obtaining FUBC was independently associated with reduced mortality (hazards ratio 0.47, 95% confidence intervals: 0.23-0.87; 0.02) after adjustments for age, chronic comorbidities, acute severity of illness, appropriateness of empirical antimicrobial therapy, and propensity to obtain FUBC. Interpretation: Improved survival in hospitalized patients with GN-BSI who had FUBC is consistent with the results of recent publications from Italy and North Carolina supporting utilization of FUBC in management of GN-BSI. Funding: This study had no funding source

Impact of Reappraisal of Fluoroquinolone Minimum Inhibitory Concentration Susceptibility Breakpoints in Gram-Negative Bloodstream Isolates

The Clinical Laboratory Standards Institute lowered the fluoroquinolone minimum inhibitory concentration (MIC) susceptibility breakpoints for and glucose non-fermenting Gram-negative bacilli in January 2019. This retrospective cohort study describes the impact of this reappraisal on ciprofloxacin susceptibility overall and in patients with risk factors for antimicrobial resistance. Gram-negative bloodstream isolates collected from hospitalized adults at Prisma Health-Midlands hospitals in South Carolina, USA, from January 2010 to December 2014 were included. Matched pairs mean difference (MD) with 95% confidence intervals (CI) were calculated to examine the change in ciprofloxacin susceptibility after MIC breakpoint reappraisal. Susceptibility of to ciprofloxacin declined by 5.2% (95% CI: -6.6, -3.8; \u3c 0.001) after reappraisal. The largest impact was demonstrated among bloodstream isolates (MD -7.8, 95% CI: -14.6, -1.1; = 0.02) despite more conservative revision in ciprofloxacin MIC breakpoints. Among antimicrobial resistance risk factors, fluoroquinolone exposure within the previous 90 days was associated with the largest change in ciprofloxacin susceptibility (MD -9.3, 95% CI: -16.1, -2.6; = 0.007). Reappraisal of fluoroquinolone MIC breakpoints has a variable impact on the susceptibility of bloodstream isolates by microbiology and patient population. Healthcare systems should be vigilant to systematically adopt this updated recommendation in order to optimize antimicrobial therapy in patients with bloodstream and other serious infections

Prediction of Fluoroquinolone Resistance in Gram-Negative Bacteria Causing Bloodstream Infections

Increasing rates of fluoroquinolone resistance (FQ-R) have limited empirical treatment options for Gram-negative infections, particularly in patients with severe beta-lactam allergy. This case-control study aims to develop a clinical risk score to predict the probability of FQ-R in Gram-negative bloodstream isolates. Adult patients with Gram-negative bloodstream infections (BSI) hospitalized at Palmetto Health System in Columbia, South Carolina, from 2010 to 2013 were identified. Multivariate logistic regression was used to identify independent risk factors for FQ-R. Point allocation in the fluoroquinolone resistance score (FQRS) was based on regression coefficients. Model discrimination was assessed by the area under receiver operating characteristic curve (AUC). Among 824 patients with Gram-negative BSI, 143 (17%) had BSI due to fluoroquinolone-nonsusceptible Gram-negative bacilli. Independent risk factors for FQ-R and point allocation in FQRS included male sex (adjusted odds ratio [aOR], 1.97; 95% confidence intervals [CI], 1.36 to 2.98; 1 point), diabetes mellitus (aOR, 1.54; 95% CI, 1.03 to 2.28; 1 point), residence at a skilled nursing facility (aOR, 2.28; 95% CI, 1.42 to 3.63; 2 points), outpatient procedure within 30 days (aOR, 3.68; 95% CI, 1.96 to 6.78; 3 points), prior fluoroquinolone use within 90 days (aOR, 7.87; 95% CI, 4.53 to 13.74; 5 points), or prior fluoroquinolone use within 91 to 180 days of BSI (aOR, 2.77; 95% CI, 1.17 to 6.16; 3 points). The AUC for both final logistic regression and FQRS models was 0.73. Patients with an FQRS of 0, 3, 5, or 8 had predicted probabilities of FQ-R of 6%, 22%, 39%, or 69%, respectively. The estimation of patient-specific risk of antimicrobial resistance using FQRS may improve empirical antimicrobial therapy and fluoroquinolone utilization in Gram-negative BSI

Empirical Fluoroquinolones Versus Broad-Spectrum Beta-Lactams for Gram-Negative Bloodstream Infections in the Absence of Antimicrobial Resistance Risk Factors

OBJECTIVES: Increasing antimicrobial resistance rates limit empirical antimicrobial treatment options for Gram-negative bloodstream infections (GN-BSI). However, antimicrobial resistance may be predicted based on patient-specific risk factors using precision medicine concepts. This retrospective, 1:2 matched cohort examined clinical outcomes in hospitalized adults without major risk factors for antimicrobial resistance receiving empirical fluoroquinolones or broad-spectrum beta-lactams (BSBL) for GN-BSI at Prisma Health-Midlands hospitals in Columbia, SC, USA from January 2010 through June 2015. METHODS: Multivariable logistic regression was used to examine early treatment failure at 72-96 h from GN-BSI. Cox proportional hazards regression was used to examine 28-day mortality and hospital length of stay (HLOS). RESULTS: Among 74 and 148 patients receiving empirical fluoroquinolones and BSBL for GN-BSI, respectively, median age was 68 years, 159 (72%) were women, and 152 (68%) had a urinary source of infection. Early treatment failure rates were comparable in fluoroquinolone and BSBL groups (27% vs. 30%, respectively, odds ratio 0.82, 95% confidence intervals [CI] 0.43-1.54, P = 0.53), as well as 28-day mortality (8.9% vs. 9.7%, respectively, hazards ratio [HR] 0.74, 95% CI 0.26-1.90, P = 0.54). Median HLOS was 6.1 days in the fluoroquinolone group and 7.1 days in the BSBL group (HR 0.73, 95% CI 0.54-0.99, P = 0.04). Transition from intravenous to oral therapy occurred sooner in the fluoroquinolone group than in the BSBL group (3.0 vs. 4.9 days, P \u3c 0.001). CONCLUSIONS: In the absence of antimicrobial resistance risk factors, fluoroquinolones provide an additional empirical treatment option to BSBL for GN-BSI. Shorter HLOS in the fluoroquinolone group may be due to earlier transition from intravenous to oral antimicrobial therapy

Pharmacist-Driven Culture and Sexually Transmitted Infection Testing Follow-Up Program in the Emergency Department

Expanding pharmacist-driven antimicrobial stewardship efforts in the emergency department (ED) can improve antibiotic management for both admitted and discharged patients. We piloted a pharmacist-driven culture and rapid diagnostic technology (RDT) follow-up program in patients discharged from the ED. This was a single-center, pre- and post-implementation, cohort study examining the impact of a pharmacist-driven culture/RDT follow-up program in the ED. Adult patients discharged from the ED with subsequent positive cultures and/or RDT during the pre- (21 August 2018–18 November 2018) and post-implementation (19 November 2018–15 February 2019) periods were screened for inclusion. The primary endpoints were time from ED discharge to culture/RDT review and completion of follow-up. Secondary endpoints included antimicrobial agent prescribed during outpatient follow-up, repeat ED encounters within 30 days, and hospital admissions within 30 days. Baseline characteristics were analyzed using descriptive statistics. Time-to-event data were analyzed using the Wilcoxon signed-rank test. One-hundred-and-twenty-seven patients were included, 64 in the pre-implementation group and 63 in the post-implementation group. There was a 36.3% reduction in the meantime to culture/RDT data review in the post-implementation group (75.2 h vs. 47.9 h, p \u3c 0.001). There was a significant reduction in fluoroquinolone prescribing in the post-implementation group (18.1% vs. 5.4%, p = 0.036). The proportion of patients who had a repeat ED encounter or hospital admission within 30 days was not significantly different between the pre- and post-implementation groups (15.6 vs. 19.1%, p = 0.78 and 9.4% vs. 7.9%, p = 1.0, respectively). Introduction of a pharmacist culture and RDT follow-up program in the ED reduced time to data review, time to outpatient intervention and outpatient follow-up of fluoroquinolone prescribing