"Electronic Phenotyping" Antimicrobials to Facilitate Outpatient Stewardship for Asymptomatic Bacteriuria and Urinary Tract Infection in Renal Transplant.

Asymptomatic bacteriuria and urinary tract infection in renal transplant are important antimicrobial stewardship targets but are difficult to identify within electronic medical records. We validated an "electronic phenotype" of antibacterials prescribed for these indications. This may be more useful than billing data in assessing antibiotic indication in this outpatient setting.

Rational Development of a Small-Molecule Activator of CK1γ2 That Decreases C99 and Beta-Amyloid Levels.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of ß-amyloid (Aß), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aß levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aß levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aß levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aß levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aß concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.

Validity of Coronavirus Disease 2019 International Classification of Diseases, Tenth Revision in the Urgent Care Setting and Impact on Antibiotic Prescribing Rates.

We validated  different coronavirus disease 2019 (COVID-19) International Classification of Diseases, Tenth Edition (ICD-10) encounter definitions across 2 urgent care clinics. Sensitivity of definitions varied throughout the pandemic. Inclusion of COVID-19 and COVID-19-like illness (CLI) ICD-10s rendered highest sensitivity but lowest specificity. Antibiotic prescribing rates were low for COVID-19 ICD-10 encounters, increasing with CLI ICD-10 encounters.

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update.

Drug dosing in obese patients continues to be challenging due to a lack of high-quality evidence to guide dosing recommendations. We first published guidance for antibiotic dosing in obese adults in 2017, in which we critically reviewed articles identified from a broad search strategy to develop dosing recommendations for 35 antimicrobials. In this updated narrative review, we searched Pubmed, Web of Science, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific generic antimicrobial names, obese, pharmacokinetics, and others. We reviewed 393 articles, cross-referenced select cited references, and when applicable, referenced drug databases, package inserts, and clinical trial data to update dosing recommendations for 41 antimicrobials. Most included articles were pharmacokinetic studies, other less frequently included articles were clinical studies (mostly small, retrospective), case reports, and very rarely, guidelines. Pharmacokinetic changes are frequently reported, can be variable, and sometimes conflicting in this population, and do not always translate to a documented difference in clinical outcomes, yet are used to inform dosing strategies. Extended infusions, high doses, and therapeutic drug monitoring remain important strategies to optimize dosing in this population. Additional studies are needed to clinically validate proposed dosing strategies, clarify optimal body size descriptors, dosing weight scalars, and estimation method of renal function in obese patients.

Risk factors and outcomes associated with persistent vancomycin resistant Enterococcal Bacteremia.

BACKGROUND: Prior studies have identified that vancomycin resistant enterococcus (VRE) bacteremia that persists for four days or more is an independent predictor of mortality. Despite this, there is no published data to identify those patients at highest risk of developing persistent VRE bacteremia. METHODS: This was a single center, retrospective, case-control study of adult patients with a VRE bloodstream infection (BSI). Case patients were those with persistent bacteremia (≥ 4 days despite VRE-directed therapy) and control patients were those with non-persistent bacteremia. Logistic regression was used to assess risk factors associated with persistent VRE BSIs. Secondary outcomes included in-hospital mortality, recurrent bacteremia, and breakthrough bacteremia. RESULTS: During the study period, 24/108 (22%) patients had persistently positive blood cultures. Risk factors for persistent bacteremia included severe neutropenia (OR 2.13), 4 out of 4 positive index blood cultures (OR 11.29) and lack of source control (OR 11.88). In an unadjusted analysis, no statistically significant differences in in-hospital mortality (58% versus 40%; p = 0.121), recurrent bacteremia (17% versus 6%; p = 0.090), or breakthrough bacteremia (13% versus 7%; p = 0.402) were observed between groups. CONCLUSION: Patients with severe neutropenia, 4 out of 4 positive index blood culture bottles, and lack of source control were more likely to develop persistent VRE bacteremia despite directed antibiotic treatment.

Sustained Reduction in Urgent Care Antibiotic Prescribing During the Coronavirus Disease 2019 Pandemic: An Academic Medical Center's Experience.

We compared antibiotic prescribing before and during the -coronavirus disease 2019 (COVID-19) pandemic at 2 academic urgent care clinics and found a sustained decrease in prescribing driven by respiratory encounters and despite transitioning to telemedicine. Antibiotics were rarely prescribed during encounters for COVID-19 or COVID-19 symptoms. COVID-19 revealed opportunities for outpatient stewardship programs.

Impact of Rapid Antimicrobial Susceptibility Testing in Gram-Negative Rod Bacteremia: a Quasi-experimental Study.

Clinical justification for rapid antimicrobial susceptibility testing (AST) in Gram-negative rod (GNR) bacteremia is compelling; however, evidence supporting its value is sparse. We investigated the impact of rapid AST on clinical and antimicrobial stewardship outcomes in real-world practice. We performed a before-and-after quasi-experimental study from February 2018 to July 2019 at a tertiary hospital of the 24-h/day, 7-day/week implementation of the direct Vitek 2 AST method from positive blood culture broth for GNR bacteremia with electronic isolate-specific de-escalation comments and daytime antibiotic stewardship program (ASP) intervention. The primary outcome was time to appropriate antibiotic escalation or de-escalation, and secondary outcomes included time to oral antibiotic stepdown, hospital length of stay (LOS), all-cause 30-day mortality, 7-day incidence of acute kidney injury (AKI), and 30-day incidence of Clostridioides difficile infection (CDI). A total of 671 GNR isolates were included from 643 adult patients. Among patients for whom antibiotic change occurred after rapid AST result, rapid AST was associated with a trend in decreased time to escalation or de-escalation (hazard ratio, 1.22; 95% confidence interval [CI], 0.99 to 1.51; P = 0.06), with median times of 52.3 versus 42.2 h. Secondary outcomes were similar in both groups and include median time to oral antibiotic stepdown, LOS, all-cause mortality, and incidence of AKI and CDI. Rapid AST led to improved stewardship measures but did not impact clinical patient outcomes. These results highlight that multiple variables in addition to the timing of the AST result contribute to clinical outcome and that further intervention may be required to clinically justify rapid AST implementation.

Development of Kinase Inactive PD173955 Analogues for Reducing Production of Aß Peptides.

Compound 3a, DV2-103, is a kinase inactive analogue of a potent Abl1/Src kinase inhibitor, PD173955, 2. Both compounds, 2 and 3a, are known to reduce production of beta amyloid (Aß) peptide in cells and animal models. We have now prepared and evaluated a series of PD-173955 analogues, several of which reduced Aß production potently. This occurs in cells expressing human full-length amyloid precursor protein (APP) and not in cells expressing APP ß-C terminal fragment (APP-C99), suggesting that the kinase inactive analogues strongly affect ß-secretase (BACE1) cleavage of APP, similarly to Gleevec. A combination of the kinase inactive analogues of PD173955 with a BACE1 inhibitor (BACEi), namely, BACE IV, strongly reduced Aß levels in cells, as noted previously with Gleevec and analogues. Several potent compounds also penetrated and accumulated in mouse brain in high nanomolar to low micromolar concentration.

Conversion from Vancomycin Trough Concentration-Guided Dosing to Area Under the Curve-Guided Dosing Using Two Sample Measurements in Adults: Implementation at an Academic Medical Center.

STUDY OBJECTIVE: The optimal pharmacodynamic parameter for the prediction of efficacy of vancomycin is the area under the concentration-time curve (AUC), and current published data indicate that dosing based on vancomycin trough concentrations is an inaccurate substitute. In this study, our objective was to compare the achievement of therapeutic target attainment after switching from a trough-based to an AUC-based dosing strategy as a part of our institution's vancomycin-per-pharmacy protocol. DESIGN: Prospective observational quality assurance study. SETTING: Academic medical center. PATIENTS: A total of 296 hospitalized adults who received vancomycin and monitoring under our institution's vancomycin-per-pharmacy protocol were included in the analysis. The preimplementation retrospective comparison group consisted of 179 patients in whom vancomycin was initiated using a trough-based dosing strategy between November 22, 2017, and January 22, 2018. The postimplementation group included 117 patients in whom vancomycin was initiated using an AUC-based dosing strategy using two-point sampling between June 19, 2018, and July 19, 2018, after hospital-wide implementation of this protocol on June 19, 2018. MEASUREMENTS AND MAIN RESULTS: AUC values were calculated from two vancomycin concentrations (peak and trough). The primary outcome was achievement of therapeutic AUC values (400-800 mg·hr/L) in the postimplementation group or therapeutic trough level values (10-20 mg/L) in the preimplementation group. Only 98 (55%) of 179 initial trough values were therapeutic in the preimplementation group (trough-only dosing method) versus 86 (73.5%) of 117 initial AUC values in the postimplementation group (AUC-based dosing method) (p=0.0014). A lower proportion of supratherapeutic AUC values was observed in the postimplementation group compared with supratherapeutic trough concentrations in the preimplementation group (1.7% vs 18%, p<0.0001). Overall, 62% of patients with initially therapeutic AUC values had subsequent trough value increases of 25% or greater, occurring at a median of 6 days of vancomycin therapy. Nephrotoxicity occurred in 11% of patients in the preimplementation versus 9.4% in the postimplementation group (p=0.70). CONCLUSION: Compared with a trough concentration-based dosing strategy, AUC-based dosing using two-point sampling improved therapeutic target attainment. Implementation is feasible at any hospital that performs vancomycin peak concentration testing and is a workable alternative to using Bayesian software for estimating AUC. This approach should also be directly compared with AUC-based dosing using Bayesian software.

Comprehensive Guidance for Antibiotic Dosing in Obese Adults.

Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogeneous results that in some cases are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations have emerged to inform antimicrobial dosing in obesity. In this narrative review, we critically review literature on dosing, PK, and possible dosing strategies in obese adults. We searched PubMed, Scopus, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific antimicrobial names, obese, pharmacokinetics, and others. We reviewed articles, cross-referenced select cited references, and when applicable, referenced drug databases and package inserts to develop dosing recommendations. We provide an overall critical review of the available data regarding PK and dosing issues including dosing recommendations in both critically ill and noncritically ill patients with significant obesity. We developed dosing recommendations for 34 antimicrobials based on 121 articles of the 2336 identified by the search strategy. Although 11 of these do not appear to require dose adjustment, obesity-specific dosing guidance is provided for the remaining 23 antimicrobials. Additional studies are needed to better understand and resolve discrepant published results regarding the PK of antibiotics to establish optimal dosing strategies in obese adults. Alternative dosing strategies, such as extended infusions, should be considered for time-dependent antibiotics (e.g., ß-lactams) in obese patients to achieve PD targets reliably. Therapeutic drug monitoring across the spectrum of antimicrobials is of increasing importance in this and other populations to ensure optimized dosing.

Evaluation of caspofungin or micafungin as empiric antifungal therapy in adult patients with persistent febrile neutropenia: a retrospective, observational, sequential cohort analysis.

BACKGROUND: Caspofungin is approved in the United States for empiric antifungal therapy for persistent febrile neutropenia (FN). There are limited data about the use of other echinocandins in this setting. OBJECTIVE: After a formulary change, we retrospectively evaluated the safety and effectiveness of caspofungin and micafungin as empiric antifungal therapy for FN at Brigham and Women's Hospital (Boston, Massachusetts). METHODS: This was a retrospective, observational, sequential cohort study. We identified patients who had received >or=2 doses on concurrent days of either caspofungin (between November 2005 and October 2006) or micafungin (between November 2006 and October 2007) for empiric FN therapy. Patients were included for analysis if they were neutropenic (absolute neutrophil count <500 cells/microL) and febrile (temperature >or=100.5 degrees F [>or=38 degrees C]). Patients without previous exposure to an echinocandin were included; those included in the caspofungin cohort were excluded from the micafungin cohort. Those who had previously received another systemic antifungal agent for FN therapy (except fluconazole for mucosal candidiasis) were excluded. Patients were followed through hospital discharge. Outcomes analyzed were successful treatment of baseline invasive fungal disease (IFD), incidence of breakthrough IFD, overall mortality, and discontinuation because of adverse events (AEs). IFD was diagnosed and classified according to current European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group criteria. RESULTS: Three hundred twenty-three patients met inclusion criteria (caspofungin, n = 149; micafungin, n = 174). Median age was 49 years in both the caspofungin and micafungin groups; 80 (53.7%) and 99 (56.9%) patients in each group, respectively, were men. Fluconazole prophylaxis had been administered to 30 patients (20.1%) treated with caspofungin and 21 patients (12.1%) treated with micafungin. Caspofungin was administered at 70 mg for one dose, followed by 50 mg daily; micafungin was administered at 100 mg daily. The median duration of therapy and of hospitalization were 10 days and 29 days, respectively, with caspofungin, and 9 days and 28 days with micafungin (both, P = NS between groups). Twelve patients (8.1%) in the caspofungin cohort and 13 (7.5%) in the micafungin cohort died during the study period (P = NS). There were 3 cases (2.0%) of baseline IFD in the caspofungin cohort and 6 (3.4%) in the micafungin cohort (P = NS); 6 were successfully treated (caspofungin, 2 [1.3% of entire group]; micafungin, 4 [2.37% of entire group]; P = NS). Breakthrough IFD was diagnosed in 16 patients (10.7%) receiving caspofungin and 21 (12.1%) receiving micafungin (P = NS). AEs requiring echinocandin discontinuation were uncommon (caspofungin, 2 cases of rash and 1 anaphylactoid infusion reaction [2.0%]; mica-fungin, 1 liver function test elevation >or=5 times the upper limit of normal and 1 maculopapular rash [1.1%]; P = NS). CONCLUSION: Micafungin, as empiric antifungal therapy for persistent FN, did not appear to differ significantly from caspofungin in terms of safety profile or efficacy in the adult patients included in this sequential cohort analysis at one institution. ClinicalTrials.gov identifier: NCT00723073.