Development of the Three Antimicrobial Stewardship E's (TASE) Framework and Association Between Stewardship Interventions and Intended Results Analysis to Identify Key Facility-Specific Interventions and Strategies for Successful Antimicrobial Stewardship.

BACKGROUND: Successful antimicrobial stewardship (AS) interventions have been described previously. Currently, a uniform operational approach to planning and implementing successful AS interventions does not exist. From 2015 to 2019, concomitant vancomycin and piperacillin-tazobactam use (CVPTU) for >48 hours at Vanderbilt University Medical Center (VUMC) significantly decreased through AS efforts. We analyzed the interventions that led to this change and created a model to inform future intervention planning and development. METHODS: Adult admissions at VUMC from January 2015 to August 2019 were evaluated for CVPTU. The percentage of admissions receiving CVPTU for >48 hours, the primary outcome, was evaluated using statistical process control charts. We created the Three Antimicrobial Stewardship E's (TASE) framework and Association between Stewardship Interventions and Intended Results (ASIR) analysis to assess potential intensity and impact of interventions associated with successful change during this time period and to identify guiding principles for development of future initiatives. RESULTS: The mean percentage of admissions receiving CVPTU per month declined from 4.2% to 0.7%. Over 8 time periods, we identified 4 periods with high, 3 with moderate, and 1 with low intervention intensity. Continuous provider-level AS education was present throughout. Creation and dissemination of division and department algorithms and reinforcement via computerized provider order entry sets preceded the largest reduction in CVPTU and sustained prescribing practice changes. CONCLUSIONS: The TASE framework and ASIR analysis successfully identified pivotal interventions and strategies needed to effect and sustain change at VUMC. Further research is needed to validate the effectiveness of this framework as a stewardship intervention planning tool at our institution and others.

Development and implementation of "handshake rounds": An antibiotic stewardship intervention for hospitalized adult patients with hematologic malignancies.

Objective: To design and implement "handshake rounds" as an antibiotic stewardship intervention to reduce inpatient intravenous (IV) antibiotic use in patients with hematologic malignancies. Design: Quasi-experimental analysis of antibiotic use (AU) and secondary outcomes before and and after handshake rounds were implemented. Setting: Quaternary-care, academic medical center. Patients: Hospitalized adults with hematologic malignancies receiving IV antibiotics. Methods: We performed a retrospective review of a preintervention cohort prior to the intervention. A multidisciplinary team developed criteria for de-escalation of antibiotics, logistics of handshake rounds, and outcome metrics. Eligible patients were discussed during scheduled handshake rounds between a hematology-oncology pharmacist and transplant-infectious diseases (TID) physician. Prospective data were collected over 30 days in the postintervention cohort. Due to small sample size, 2:1 matching was used to compare pre- to and postintervention AU. Total AU in days of therapy per 1,000 patient days (DOT/1,000 PD) was reported. Mean AU per patient was analyzed using Wilcoxon rank-sum test. A descriptive analysis of secondary outcomes of pre- and postintervention cohorts was performed. Results: Total AU was substantially lower after the intervention, with 517 DOT/1,000 PD compared to 865 DOT/1,000 PD before the intervention. There was no statistically significant difference in the mean AU per patient between the 2 cohorts. There was a lower rate of 30-day mortality in the postintervention cohort and rates of ICU admissions were similar. Conclusions: Conducting handshake rounds is a safe and effective way to implement an antibiotic stewardship intervention among high-risk patient population such as those with hematologic malignancies.

Association of antibiotics with veteran visit satisfaction and antibiotic expectations for upper respiratory tract infections.

Background and objective: Veterans' Affairs (VA) healthcare providers perceive that Veterans expect and base visit satisfaction on receiving antibiotics for upper respiratory tract infections (URIs). No studies have tested this hypothesis. We sought to determine whether receiving and/or expecting antibiotics were associated with Veteran satisfaction with URI visits. Methods: This cross-sectional study included Veterans evaluated for URI January 2018-December 2019 in an 18-clinic ambulatory VA primary-care system. We evaluated Veteran satisfaction via the Patient Satisfaction Questionnaire Short Form (RAND Corporation), an 18-item 5-point Likert scale survey. Additional items assessed Veteran antibiotic expectations. Antibiotic receipt was determined via medical record review. We used multivariable regression to evaluate whether antibiotic receipt and/or Veteran antibiotic expectations were associated with satisfaction. Subgroup analyses focused on Veterans who accurately remembered antibiotic prescribing during their URI visit. Results: Of 1,329 eligible Veterans, 432 (33%) participated. Antibiotic receipt was not associated with differences in mean total satisfaction (adjusted score difference, 0.6 points; 95% confidence interval [CI], -2.1 to 3.3). However, mean total satisfaction was lower for Veterans expecting an antibiotic (adjusted score difference -4.4 points; 95% CI -7.2 to -1.6). Among Veterans who accurately remembered the visit and did not receive an antibiotic, those who expected an antibiotic had lower mean satisfaction scores than those who did not (unadjusted score difference, -16.6 points; 95% CI, -24.6 to -8.6). Conclusions: Veteran expectations for antibiotics, not antibiotic receipt, are associated with changes in satisfaction with outpatient URI visits. Future research should further explore patient expectations and development of patient-centered and provider-focused interventions to change patient antibiotic expectations.

Changes in antimicrobial utilization during the coronavirus disease 2019 (COVID-19) pandemic after implementation of a multispecialty clinical guidance team.

OBJECTIVE: Evaluate changes in antimicrobial use during COVID-19 and after implementation of a multispecialty COVID-19 clinical guidance team compared to pre-COVID-19 antimicrobial use. DESIGN: Retrospective observational study. SETTING: Tertiary-care academic medical center. PARTICIPANTS: Internal medicine and medical intensive care unit (MICU) provider teams and hospitalized COVID-19 patients. METHODS: Difference-in-differences analyses of antibiotic days of therapy per 1,000 patient days present (DOT) for internal medicine and MICU teams treating COVID-19 patients versus teams that did not were performed for 3 periods: before COVID-19, initial COVID-19 period, and after implementation of a multispecialty COVID-19 clinical guidance team which included daily, patient-specific antimicrobial stewardship recommendations. Patient characteristics associated with antibiotic DOT were evaluated using multivariable Poisson regression. RESULTS: In the initial COVID-19 period, compared to the pre-COVID-19 period, internal medicine and MICU teams increased weekly antimicrobial use by 145.3 DOT (95% CI, 35.1-255.5) and 204.0 DOT (95% CI, -16.9 to 424.8), respectively, compared to non-COVID-19 teams. In the intervention period, internal medicine and MICU COVID-19 teams both had significant weekly decreases of 362.3 DOT (95% CI, -443.3 to -281.2) and 226.3 DOT (95% CI, -381.2 to -71.3). Of 131 patients hospitalized with COVID-19, 86 (65.6%) received antibiotics; no specific patient factors were significantly associated with an expected change in antibiotic days. CONCLUSIONS: Antimicrobial use initially increased for COVID-19 patient care teams compared to pre-COVID-19 levels but significantly decreased after implementation of a multispecialty clinical guidance team, which may be an effective strategy to reduce unnecessary antimicrobial use.

Antimicrobial de-escalation in patients with high-risk febrile neutropenia: Attitudes and practices of adult hospital care providers.

In a survey of adult hospital providers regarding antibiotic use in the treatment of febrile neutropenia, clinical fellows, and pharmacists showed higher comfort levels with early antimicrobial de-escalation compared to hematology-oncology and transplant infectious diseases physicians. These frontline team members are ideal partners to champion antimicrobial stewardship interventions in febrile neutropenia.

Creating a Framework to Integrate Residency Program and Medical Center Approaches to Quality Improvement and Patient Safety Training.

Quality improvement and patient safety (QIPS) are core components of graduate medical education (GME). Training programs and affiliated medical centers must partner to create an environment in which trainees can learn while meaningfully contributing to QIPS efforts, to further the shared goal of improving patient care. Numerous challenges have been identified in the literature, including lack of resources, lack of faculty expertise, and siloed QIPS programs. In this article, the authors describe a framework for integrated QIPS training for residents in the University of Washington Internal Medicine Residency Program, beginning in 2014 with the creation of a dedicated QIPS chief resident position and assistant program director for health systems position, the building of a formal curriculum, and integration with medical center QIPS efforts. The postgraduate year (PGY) 1 curriculum focused on the culture of patient safety and entering traditional patient safety event (PSE) reports. The PGY-2 curriculum highlighted QIPS methodology and how to conduct mentored PSE reviews of cases that were of educational value to trainees and a clinical priority to the medical center. Additional PGY-2/PGY-3 training focused on the active report, presentation, and evaluation of cases during morbidity and mortality conferences while on clinical services, as well as how to lead longitudinal QIPS work. Select residents led mentored QI projects as part of an additional elective. The hallmark feature of this framework was the depth of integration with medical center priorities, which maximized educational and operational value. Evaluation of the program demonstrated improved attitudes, knowledge, and behavior changes in trainees, and significant contributions to medical center QIPS work. This specialty-agnostic framework allowed for training program and medical center integration, as well as horizontal integration across GME specialties, and can be a model for other institutions.

A Narrative Review of Early Oral Stepdown Therapy for the Treatment of Uncomplicated Staphylococcus aureus Bacteremia: Yay or Nay?

Historically, intravenous (IV) antibiotics have been the cornerstone of treatment for uncomplicated Staphylococcus aureus bacteremia (SAB). However, IV antibiotics are expensive, increase the rates of hospital readmission, and can be associated with catheter-related complications. As a result, the potential role of oral antibiotics in the treatment of uncomplicated SAB has become a subject of interest. This narrative review article aims to summarize key arguments for and against the use of oral antibiotics to complete treatment of uncomplicated SAB and evaluates the available evidence for specific oral regimens. We conclude that evidence suggests that oral step-down therapy can be an alternative for select patients who meet the criteria for uncomplicated SAB and will comply with medical treatment and outpatient follow-up. Of the currently studied regimens discussed in this article, linezolid has the most support, followed by fluoroquinolone plus rifampin.

Analysis of a high-prescribing state's 2016 outpatient antibiotic prescriptions: Implications for outpatient antimicrobial stewardship interventions.

OBJECTIVE: To identify prescriber characteristics that predict antibiotic high-prescribing behavior to inform statewide antimicrobial stewardship interventions. DESIGN: Retrospective analysis of 2016 IQVIA Xponent, formerly QuintilesIMS, outpatient retail pharmacy oral antibiotic prescriptions in Tennessee. SETTING: Statewide retail pharmacies filling outpatient antibiotic prescriptions. PARTICIPANTS: Prescribers who wrote at least 1 antibiotic prescription filled at a retail pharmacy in Tennessee in 2016. METHODS: Multivariable logistic regression, including prescriber gender, birth decade, specialty, and practice location, and patient gender and age group, to determine the association with high prescribing. RESULTS: In 2016, 7,949,816 outpatient oral antibiotic prescriptions were filled in Tennessee: 1,195 prescriptions per 1,000 total population. Moreover, 50% of Tennessee's outpatient oral antibiotic prescriptions were written by 9.3% of prescribers. Specific specialties and prescriber types were associated with high prescribing: urology (odds ratio [OR], 3.249; 95% confidence interval [CI], 3.208-3.289), nurse practitioners (OR, 2.675; 95% CI, 2.658-2.692), dermatologists (OR, 2.396; 95% CI, 2.365-2.428), physician assistants (OR, 2.382; 95% CI, 2.364-2.400), and pediatric physicians (OR, 2.340; 95% CI, 2.320-2.361). Prescribers born in the 1960s were most likely to be high prescribers (OR, 2.574; 95% CI, 2.532-2.618). Prescribers in rural areas were more likely than prescribers in all other practice locations to be high prescribers. High prescribers were more likely to prescribe broader-spectrum antibiotics (P < .001). CONCLUSIONS: Targeting high prescribers, independent of specialty, degree, practice location, age, or gender, may be the best strategy for implementing cost-conscious, effective outpatient antimicrobial stewardship interventions. More information about high prescribers, such as patient volumes, clinical scope, and specific barriers to intervention, is needed.

Lateralized suppression of dichotically presented digits after commissural section in man.

Right-handed patients with surgical disconnection of the cerebral hemispheres cannot report verbal input to the left ear if diferent verbal stimuli have been channeled simultaneously to the right ear. With monaural stimulation, they show equal accuracy of report for the two ears. These findings highlight the dominance of the contralateral over the ipsilateral auditory projection system. Suppression of right-ear input is obtained in nonverbal tests. Dissociation between verbal and left-hand stereognostic responses indicate a right-left dichotomy for auditory experience in the disconnected hemispheres.

Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936.

Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig/TCR rearrangement patterns as well as t(14;18) and t(11;14) translocations of 369 B-cell malignancies belonging to five WHO-defined entities using the standardized BIOMED-2 multiplex PCR tubes accompanied by international pathology panel review. B-cell clonality was detected by combined use of the IGH and IGK multiplex PCR assays in all 260 definitive cases of B-cell chronic lymphocytic leukemia (n=56), mantle cell lymphoma (n=54), marginal zone lymphoma (n=41) and follicular lymphoma (n=109). Two of 109 cases of diffuse large B-cell lymphoma showed no detectable clonal marker. The use of these techniques to assign cell lineage should be treated with caution as additional clonal TCR gene rearrangements were frequently detected in all disease categories. Our study indicates that the BIOMED-2 multiplex PCR assays provide a powerful strategy for clonality assessment in B-cell malignancies resulting in high Ig clonality detection rates particularly when IGH and IGK strategies are combined.

p53 mutation is a common genetic event in ovarian carcinoma.

Using the single-strand conformational polymorphism technique, we have screened 66 malignant ovarian tumors for p53 mutation in exons 5 to 8. Thirty-four of the tumors demonstrated a single-strand conformational polymorphism band shift in this region of the gene, including 6 in exon 5, 7 in exon 6, 12 in exon 7, and 10 in exon 8 (one of the tumors showed a shift for exons 7 and 8). All of the single-strand conformational polymorphism shifts have been further characterized by DNA sequencing, and 31 of 35 have been shown to represent genuine DNA alterations. These include 27 point mutations (23 missense, 2 nonsense, and 2 silent mutations), 3 deletions (a 2-base pair deletion introducing, by frameshift, a stop codon further downstream; a 3-base pair deletion; and an unusual 6-base pair deletion made up of separate 2-base pair and 4-base pair deletions), and a 4-base pair insertion (introducing a stop codon downstream). In total, 29 of the 66 (44%) carcinomas analyzed had mutations affecting the primary sequence of the p53 protein. p53 mutation was found in tumors of all International Federation of Gynecologists and Obstetricians stages, suggesting that it might be an earlier genetic event in the progression of epithelial ovarian tumors than previously thought. A significantly greater number of p53 mutations were seen in high-grade serous carcinomas than in those of endometrioid and mucinous types (0.02 > P > 0.01). Analysis of the distribution of point mutations showed no preference for any particular mutation type.

Phenotypic Characterization of Insulin-Resistant and Insulin-Sensitive Obesity.

CONTEXT: Whereas insulin resistance and obesity coexist, some obese individuals remain insulin sensitive. OBJECTIVE: We examined phenotypic and metabolic factors associated with insulin sensitivity in both muscle and liver in obese individuals. DESIGN AND PARTICIPANTS: Sixty-four nondiabetic obese adults (29 males) underwent hyperinsulinemic (15 and 80 mU/m(2) · min)-euglycemic clamps with deuterated glucose. Top tertile subjects for glucose infusion rate during the high-dose insulin clamp were assigned Musclesen and those in the lower two tertiles were assigned Muscleres. Secondarily, top tertile subjects for endogenous glucose production suppression during the low-dose insulin clamp were deemed Liversen and the remainder Liverres. MAIN OUTCOMES MEASURES: Clinical and laboratory parameters and visceral, subcutaneous, liver, and pancreatic fat were compared. RESULTS: Musclesen and Muscleres had similar body mass index and total fat (P > .16), but Musclesen had lower glycated hemoglobin (P < .001) and systolic (P = .01) and diastolic (P = .03) blood pressure (BP). Despite similar sc fat (P = 1), Musclesen had lower visceral (P < .001) and liver (P < .001) fat. Liversen had lower visceral (P < .01) and liver (P < .01) fat and C-reactive protein (P = .02) than Liverres. When subjects were grouped by both glucose infusion rate during the high-dose insulin clamp and endogenous glucose production suppression, insulin sensitivity at either muscle or liver conferred apparent protection from the adverse metabolic features that characterized subjects insulin resistant at both sites. High-density lipoprotein-cholesterol, 1-hour glucose, systolic BP, and triglycerides explained 54% of the variance in muscle insulin sensitivity. CONCLUSIONS: Obese subjects who were insulin sensitive at muscle and/or liver exhibited favorable metabolic features, including lower BP, liver and visceral adiposity. This study identifies factors associated with, and possibly contributing to, insulin sensitivity in obesity.

A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR.

Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/µl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).

Teaching undergraduates about familial breast cancer: comparison of a computer assisted learning (CAL) package with a traditional tutorial approach.

We have developed a computer assisted learning package for teaching clinical medical students about familial breast cancer. It explains the principles of genetic predisposition to breast cancer, the association with other cancers, the principles of family history taking and confirmation, risk assessment and possible interventions. Clinical medical students were randomised to either conventional teaching or CAL, 48 students attended the evaluation session. Students randomised to conventional teaching received a 20 min mini-lecture, those randomised to CAL completed the package with technical, but not academic support available. At the end of the intervention both groups of students completed a short written assessment of acceptability and knowledge and understanding of breast cancer genetics. There was no significant difference between the CAL and mini-lecture groups in terms of marks or acceptability. Thus CAL appears to be an acceptable and effective method of teaching clinical medical students about familial breast cancer. Although time consuming to develop, CAL can be used in a variety of settings to increase curriculum flexibility. Methods of motivating students to complete the CAL, and of providing educational support are being explored.

Polymorphisms in P21CIP1/WAF1 are not correlated with TP53 status in sporadic ovarian tumours.

In breast cancers and sarcomas, a variant polymorphism in the cell cycle inhibitor P21CIP1/WAF1 is under-represented in those individuals whose tumours contain mutated TP53. The aim of this study was to determine whether this variant polymorphism was also under-represented in those with ovarian carcinoma and TP53 mutations. We studied lymphocyte DNA from 104 women with ovarian carcinoma, 15 with borderline tumours and 16 with benign tumours, using a previously-reported PCR-RFLP technique. 96 of the ovarian carcinoma cases had been previously examined for mutations in TP53 and/or for overexpression of the TP53 protein. The variant allele was seen in 11 out of 104 women (10.6%) with ovarian carcinoma. There was no significant difference in the distribution of the variant allele in the women whose tumours had (7/47) or did not have (4/49) TP53 mutations (P = 0.523). It does not appear that the presence of this variant allele of P21CIP1/WAF1 has any aetiological role in ovarian carcinomas. Studies in other tumours support this finding.

Cognitive risk-taking after frontal or temporal lobectomy--II. The synthesis of phonemic and semantic information.

Patients with unilateral cerebral excisions and control subjects performed two tasks in which target words had to be guessed on the basis of either phonemic or semantic partial-information clues. Each cumulatively provided clue was assigned successively lower point-value, these points being risked whenever the subject responded. Patients with frontal-lobe excisions chose to make a guess after seeing only one clue more often than did a combined group of subjects without frontal-lobe damage, but this guessing-score was also related to extent of right temporal-lobe removal. Patients with left temporal-lobe or left frontal-lobe lesions had difficulty solving the verbal clues, occasionally failing to recognize that a response generated in the context of one clue satisfied all the clues.

Performance of complex arm movements and facial-movement sequences after cerebral commissurotomy.

Two patients with presumed complete midline section of the interhemispheric commissures and two patients with partial section were asked to copy complex arm movements and facial-movement sequences. Their performance was compared with our previously published findings on these tasks for patients with unilateral removals from the frontal, temporal or parietal region. On the arm-movement task, the commissurotomized patients were impaired equally with either the left or right arm and were as poor at performing this task as patients with excisions of left parietal cortex. On the face-movement task, commissurotomized patients performed very poorly, scoring significantly lower than all excision groups. There was no significant difference on either task between the performance of the patients with partial and those with complete sections.

Effects of frontal or temporal lobectomy on the use of advance information in a choice reaction time task.

The ability to make use of directional cues presented to subjects before they are asked to make a specific response was studied in 69 patients who had undergone a unilateral frontal or temporal lobe excision, and in 24 normal control subjects. Choice reaction time was measured in two conditions: (1) informative, where a centrally presented cue indicated in advance the target's location, and (2) neutral, where the cue was a symbol carrying no directional information. Patients with excisions from the left or right frontal lobe did not benefit from the available information to the same extent as patients with either left or right temporal lobe excisions or normal control subjects.

The role of the left hippocampal region in the acquisition and retention of story content.

Thirteen normal control subjects and 62 patients who had undergone either a unilateral temporal or a unilateral frontal lobectomy learned the content of a short prose passage to a strict criterion. Compared to other subject, patients with left temporal-lobe excision took longer to learn the story content and, within this group, the slowest rate noted was for patients with extensive removal from the hippocampal region. When retention of the material was tested after a 20 min delay, only the group with large excisions from the left hippocampus and/or parahippocampal gyrus was impaired. This finding of abnormally rapid forgetting of material learned to criterion highlights the role of the left hippocampal region in the long-term maintenance of verbal information presented in a context.