Efficacy of Eravacycline Versus Best Previously Available Therapy for Adults With Pneumonia Due to Difficult-to-Treat Resistant (DTR) Acinetobacter baumannii.

BACKGROUND: Multidrug-resistant Acinetobacter baumannii remains challenging to treat. Although eravacycline has in vitro activity against this pathogen, there are no studies evaluating outcomes. OBJECTIVE: To assess the efficacy of eravacycline compared with best previously available therapy in adults with difficult-to-treat resistant (DTR) A. baumannii pneumonia. METHODS: This was a retrospective study of adults hospitalized for pneumonia with DTR A. baumannii. Patients receiving eravacycline were compared with those receiving best previously available therapy. The primary outcome was 30-day in-hospital mortality. Secondary outcomes included clinical cure at Day 14, hospital and intensive care unit (ICU) length of stay, microbiologic cure, and readmission within 90 days with a positive A. baumannii respiratory culture. RESULTS: Ninety-three patients were included, with 27 receiving eravacycline. Eravacycline was associated with higher 30-day mortality (33% vs 15%; P = 0.048), lower microbiologic cure (17% vs 59%; P = 0.004), and longer durations of mechanical ventilation (10.5 vs 6.5 days; P = 0.016). At baseline, eravacycline patients had more A. baumannii bacteremia and coinfection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Among bacteremic patients, all 4 receiving eravacycline died by Day 30 and both patients receiving best previously available therapy survived. Upon exclusion of patients with bacteremia and SARS-CoV-2, there were no differences between the groups across any outcomes. CONCLUSIONS: Eravacycline-based combination therapy had similar outcomes to best previously available combination therapy for adults with DTR A. baumannii pneumonia. However, eravacycline should be used with caution in the setting of bacteremia as outcomes were poor in this population.

Multicenter Retrospective Review of Ketamine Use in the ICU.

The response of ICU patients to continuously infused ketamine when it is used for analgesia and/or sedation remains poorly established. OBJECTIVES: To describe continuous infusion (CI) ketamine use in critically ill patients, including indications, dose and duration, adverse effects, patient outcomes, time in goal pain/sedation score range, exposure to analgesics/sedatives, and delirium. DESIGN SETTING AND PARTICIPANTS: Multicenter, retrospective, observational study from twenty-five diverse institutions in the United States. Patients receiving CI ketamine between January 2014 and December 2017. MAIN OUTCOMES AND MEASURES: Chart review evaluating institutional and patient demographics, ketamine indication, dose, administration, and adverse effects. Pain/sedation scores, cumulative doses of sedatives and analgesics, and delirium screenings in the 24 hours prior to ketamine were compared with those at 0-24 hours and 25-48 hours after. RESULTS: A total of 390 patients were included (median age, 54.5 yr; interquartile range, 39-65 yr; 61% males). Primary ICU types were medical (35.3%), surgical (23.3%), and trauma (17.7%). Most common indications were analgesia/sedation (n = 357, 91.5%). Starting doses were 0.2 mg/kg/hr (0.1-0.5 mg/kg/hr) and continued for 1.6 days (0.6-2.9 d). Hemodynamics in the first 4 hours after ketamine were variable (hypertension 24.0%, hypotension 23.5%, tachycardia 19.5%, bradycardia 2.3%); other adverse effects were minimal. Compared with 24 hours prior, there was a significant increase in proportion of time spent within goal pain score after ketamine initiation (24 hr prior: 68.9% [66.7-72.6%], 0-24 hr: 78.6% [74.3-82.5%], 25-48 hr: 80.3% [74.6-84.3%]; p < 0.001) and time spent within goal sedation score (24 hr prior: 57.1% [52.5-60.0%], 0-24 hr: 64.1% [60.7-67.2%], 25-48 hr: 68.9% [65.5-79.5%]; p < 0.001). There was also a significant reduction in IV morphine (mg) equivalents (24 hr prior: 120 [25-400], 0-24 hr: 118 [10-363], 25-48 hr: 80 [5-328]; p < 0.005), midazolam (mg) equivalents (24 hr prior: 11 [4-67], 0-24 hr: 6 [0-68], 25-48 hr: 3 [0-57]; p < 0.001), propofol (mg) (24 hr prior: 942 [223-4,018], 0-24 hr: 160 [0-2,776], 25-48 hr: 0 [0-1,859]; p < 0.001), and dexmedetomidine (µg) (24 hr prior: 1,025 [276-1,925], 0-24 hr: 285 [0-1,283], 25-48 hr: 0 [0-826]; p < 0.001). There was no difference in proportion of time spent positive for delirium (24 hr prior: 43.0% [17.0-47.0%], 0-24 hr: 39.5% [27.0-43.8%], 25-48 hr: 0% [0-43.7%]; p = 0.233). Limitations to these data include lack of a comparator group, potential for confounders and selection bias, and varying pain and sedation practices that may have changed since completion of the study. CONCLUSIONS AND RELEVANCE: There is variability in the use of CI ketamine. Hemodynamic instability was the most common adverse effect. In the 48 hours after ketamine initiation compared with the 24 hours prior, proportion of time spent in goal pain/sedation score range increased and exposure to other analgesics/sedatives decreased.

Ten Tips for Pharmacy Faculty Members for Successfully Navigating Promotion and Tenure.

This paper presents 10 key tips or recommendations for successful navigation of the promotion and tenure process. The 10 key tips are: know institutional expectations, develop an action plan at least two to three years in advance; identify your balance of teaching, scholarship, service; synergize activities and develop a niche; prioritize time to activities of high-impact to promotion and tenure; track achievements in the format expected for promotion and tenure application; seek out faculty guidance on promotion and tenure; meet with mentor(s) regularly to review progress; have a well-written personal statement; and have your final dossier reviewed by colleagues. Faculty members are more likely to be successful through timely and appropriate planning, balancing and synergizing activities, tracking activities and achievements, developing a well-written personal statement, and requesting help from experienced colleagues.

Evaluation of Guideline Recommendations for Dual Antipseudomonal Therapy in Hospitalized Adults with Pneumonia Using Combination Antibiograms.

BACKGROUND: Guidelines for pneumonia recommend empiric dual antipseudomonal therapy in patients with specific risk factors. However, there is lack of consensus on when to use dual antipseudomonal therapy as the recommendations are rated as weak, based on low-quality evidence. OBJECTIVES: The objectives of this study were to develop combination antibiograms to assess the susceptibility of Pseudomonas aeruginosa (P. aeruginosa) in respiratory cultures to combinations of empiric antibiotics and to use combination antibiograms to delineate the impact of specific risk factors for which guidelines recommend dual antipseudomonal therapy. METHODS: A retrospective cohort study was conducted of adults hospitalized with pneumonia with positive respiratory cultures for P. aeruginosa between September 2014 and September 2018. Data collected included demographics, antimicrobial susceptibility results, and risk factors for which guidelines recommend dual antipseudomonal therapy. Combination antibiograms were developed and logistic regression was performed to identify risk factors for nonsusceptibility to beta-lactams. RESULTS: Eight hundred nineteen patients were included and 72% received antibiotics. Beta-lactam susceptibility ranged from 58% to 69% and addition of a fluoroquinolone or aminoglycoside resulted in statistically significant increases in susceptibility. However, only addition of tobramycin or amikacin provided susceptibility rates approaching or exceeding 90% stratified by pneumonia type and risk factors. Presence of guideline-based risk factors generally resulted in reduced susceptibility rates. Logistic regression identified three risk factors associated with nonsusceptibility to beta-lactams: intravenous antibiotics in the previous 90 days, nursing home residence, and mechanical ventilation at onset. The cumulative presence of each additional risk factor affected beta-lactam susceptibility rates, which were 93% in the absence of any risk factors and 39% when all three risk factors co-existed. CONCLUSIONS: Risk factors necessitating dual antipseudomonal therapy for pneumonia should be locally validated. When dual antipseudomonal therapy is indicated, tobramycin or amikacin have the best likelihood of providing adequate in vitro activity.

The Current Landscape of College-Sponsored Postgraduate Teaching and Learning Curriculum Programs.

Objective. To describe the landscape of teaching and learning curriculum (TLC) programs sponsored by US schools and colleges of pharmacy and evaluate their adoption of best practice recommendations. Methods. A 28-item electronic survey instrument was developed based on best practice recommendations published by the American Association of Colleges of Pharmacy (AACP), American Society of Health-System Pharmacists (ASHP), and American College of Clinical Pharmacy (ACCP) for the conduct of TLC programs. The survey instrument was electronically distributed to 137 accredited colleges and schools of pharmacy in the United States. Results. Eighty-eight institutions responded, resulting in a response rate of 64%. Sixty-one TLC programs were included in the final analysis. Seventy-five percent of TLC programs reported using best practice recommendations; however, 10% of respondents indicated they were not aware of the published recommendations. Inconsistencies among programs were noted in required teaching experiences, participant evaluation, and ongoing programmatic assessment. Conclusion. Most institutions offering TLC programs are aware of published best practice guidelines and have adopted a majority of the published best practices. However, considerable variability exists across the country. Development of a formal external validation process for TLC programs is necessary to ensure consistent quality.

Qualitative Analysis of the Impact of Changes to the Student Evaluation of Teaching Process.

Objective. To determine how changes to the student evaluation of teaching (SET) survey instrument and process at a college of pharmacy contributed to improved student response rates and to understand how the process could be further refined. Methods. Pharmacy students from the class of 2018 who had participated in both the old and new SET process were recruited to participate in one of four focus group interviews. An inductive approach was used for data collection and analysis. A focus group guide was created based on two major domains: comparing changes between the old and new SET process and survey form, and determining how the new SET process could be further refined. Results. In South Jordan, UT, six students participated in one of the focus groups and seven students participated in the other focus group. In Henderson, NV, seven students participated in each of the two focus groups. Twenty-seven total students participated in the four focus groups across two campuses. Students stated that reducing the number of questions on each SET survey instrument and using a 5-point rather than a 10-point Likert scale were positive changes. The changes also motivated them to complete the surveys, which improved overall response rates. Although students reported that the monetary incentive (contributions toward the cost of the class banquet) that had been added to the new SET process was a strong motivator, the incentive itself would have likely been insufficient without the other changes. Several participants stated that receiving feedback from faculty members on changes made to teaching materials based upon previous student evaluations was also an important motivator for students to continue completing the surveys. Conclusion. Students identified several motivators for SET participation. Improving the process for survey completion is essential to improve response rates to more accurately represent the feedback of the entire student body. Additionally, the evaluation process must ensure that the data gathered are robust, accurate, and insightful, to be of good use of student and faculty time.

Motivators, barriers, and strategies to improve response rate to student evaluation of teaching.

INTRODUCTION: Student evaluation of teaching (SET) is a tool that most pharmacy schools use to evaluate faculty. After multiple years of low response rates to SET, Roseman University began a process to identify motivators, barriers, and strategies to improve SET response rates. Multiple strategies were implemented and response rate was analyzed to determine if the changes were effective. METHODS: A modified Delphi process was used to identify motivators, barriers, and strategies to improve SET response rates. Faculty, students, and administration engaged in a year-long process involving four distinct phases to build consensus regarding SET implementation and processes. The process was implemented and then response rates were evaluated the following academic year. RESULTS: Barriers included frequency of surveys, length of surveys, length of rating scale, ambiguity of questions, misunderstanding on importance of SET, and lack of perceived benefit for completion of SET. For each pharmacy class, response rates increased two to three times baseline (p < 0.05). For all classes combined, response rates significantly increased from 24% to 66%. CONCLUSIONS: The modified Delphi process successfully identified barriers, motivators, and strategies for improving SET. Additionally, the process built consensus that led to successful implementation of the new SET with significantly improved response rates.

Evaluation of a Modified Debate Exercise Adapted to the Pedagogy of Team-Based Learning.

Objective. To assess the impact of a debate exercise on self-reported evidence of student learning in literature evaluation, evidence-based decision making, and oral presentation. Methods. Third-year pharmacy students in a required infectious disease therapeutics course participated in a modified debate exercise that included a reading assignment and readiness assessment tests consistent with team-based learning (TBL) pedagogy. Peer and faculty assessment of student learning was accomplished with a standardized rubric. A pre- and post-debate survey was used to assess self-reported perceptions of abilities to perform skills outlined by the learning objectives. Results. The average individual readiness assessment score was 93.5% and all teams scored 100% on their team readiness assessments. Overall student performance on the debates was also high with an average score of 88.2% prior to extra credit points. Of the 95 students, 88 completed both pre- and post-surveys (93% participation rate). All learning objectives were associated with a statistically significant difference between pre- and post-debate surveys with the majority of students reporting an improvement in self-perceived abilities. Approximately two-thirds of students enjoyed the debates exercise and believed it improved their ability to make and defend clinical decisions. Conclusion. A debate format adapted to the pedagogy of TBL was well-received by students, documented high achievement in assessment of skills, and improved students' self-reported perceptions of abilities to evaluate the literature, develop evidence-based clinical decisions, and deliver an effective oral presentation.

Development of a bedside scoring system for predicting a first recurrence of Clostridium difficile-associated diarrhea.

PURPOSE: A scoring system for identifying patients at high or low risk for recurrent Clostridium difficile-associated diarrhea (CDAD) is described. METHODS: A retrospective cohort study was performed using data on adults with CDAD admitted to a 3-hospital system from 2009 to 2014. The primary endpoint was the rate of recurrent CDAD within 60 days of clinical cure of CDAD. Risk factors for CDAD recurrence were identified, and a risk prediction tool was developed using multivariate logistic regression. RESULTS: The CDAD cure rate in the study cohort (n = 340) was 92.3%; the 60-day recurrence rate was 16.9%. Five factors were significantly associated with high recurrence risk: presence of CDAD at admission, body temperature of >37.8 °C at admission, leukocytosis, nosocomial CDAD, and abdominal distention on CDAD presentation. From that information a risk prediction tool, the CDAD "recurrence score," was developed (1 point is assigned for each factor present, for a maximum score of 5). Validation testing of the recurrence score indicated an area under the receiver operating characteristic curve of 0.72 (95% confidence interval, 0.65-0.80). A score of ≥2 had a negative predictive value of 91%, while a score of ≥4 had a positive predictive value of 70%. CONCLUSION: If externally validated in future studies, a tool for predicting the risk of recurrent CDAD using data readily available at the time of presentation could allow clinicians to identify patients at high risk for recurrence, address modifiable risk factors, and select tailored treatments to improve patient outcomes.

The prevalence and implications of BK virus replication in non-renal solid organ transplant recipients: A systematic review.

The significance of BK viruria and viremia in non-renal solid organ transplants is poorly understood. A systematic review was performed reviewing the incidence and implications of BK virus replication in non-renal solid organ transplants. Ninety-seven studies were identified, of which 18 including lung, heart, liver and pancreas transplants were included. The overall incidence of BK viruria and viremia was 20% and 3% respectively and 17 cases of BK nephropathy were identified. Heart transplant recipients had a higher overall incidence of BK viremia than other non-renal organ types, and the majority of cases of BK virus-associated nephropathy were in heart transplant recipients. The incidence of BK viremia was significantly lower in non-renal solid organ transplants than that of renal transplant recipients and BK virus-associated nephropathy was rare. BK virus-associated nephropathy may be considered in heart transplant recipients who have unexplained and persistent renal dysfunction not attributable to other causes.

Unpredictable absorption of oral opioid medications in a quadriplegic patient with chronic enterocutaneous fistulas.

Although there is an abundance of literature on the acute management of enterocutaneous fistulas, there is a paucity of data on the chronic management of enterocutaneous fistulas. Their impact on oral pharmacotherapy, including their effect on the bioavailability of oral medications, is poorly understood. This case describes a 23-year-old quadriplegic male with a complex history of multiple abdominal surgeries presented with three persistent enterocutaneous fistulas. Diazepam and furosemide were among the patient's oral medications and had sufficient bioavailability to show efficacy on anxiety and pedal edema, respectively. Conversely, oral oxycodone and methadone were ineffective in controlling chronic pain despite high doses and aggressive titration. Due to inadequate pain control, the patient supplemented opioid medications with high doses of lorazepam and diazepam to augment psychological comfort. A trial of subcutaneous morphine successfully produced immediate analgesia, causing a marked reduction in benzodiazepine use. Enterocutaneous fistulas may reduce the bioavailability of oral medications to various degrees depending upon the medication. Further research is needed to elucidate the effect chronic enterocutaneous fistulas have on the bioavailability of oral medications. It is therefore important for clinicians to question the bioavailability of medications in the setting of enterocutaneous fistulas and poor clinical response.

DNA cleavage induced by antitumor antibiotic leinamycin and its biological consequences.

The natural product leinamycin has been found to produce abasic sites in duplex DNA through the hydrolysis of the glycosidic bond of guanine residues modified by this drug. In the present study, using a synthetic oligonucleotide duplex, we demonstrate spontaneous DNA strand cleavage at leinamycin-induced abasic sites through a ß-elimination reaction. However, methoxyamine modification of leinamycin-induced abasic sites was found to be refractory to the spontaneous ß-elimination reaction. Furthermore, this complex was even resistant to the δ-elimination reaction with hot piperidine treatment. Bleomycin and methyl methanesulfonate also induced strand cleavage in a synthetic oligonucleotide duplex even without thermal treatment. However, methoxyamine has a negligible effect on DNA strand cleavage induced by both drugs, suggesting that the mechanism of DNA cleavage induced by leinamycin might be different from those induced by bleomycin or methyl methanesulfonate. In this study, we also assessed the cytotoxicity of leinamycin against a collection of mammalian cell lines defective in various repair pathways. The mammalian cell line defective in the nucleotide excision repair (NER) or base excision repair (BER) pathways was about 3 to 5 times more sensitive to leinamycin as compared to the parental cell line. In contrast, the radiosensitive mutant xrs-5 cell line deficient in V(D)J recombination showed similar sensitivity towards leinamycin compared to the parental cell line. Collectively, our findings suggest that both NER and BER pathways play an important role in the repair of DNA damage caused by leinamycin.

Characterization of DNA damage induced by a natural product antitumor antibiotic leinamycin in human cancer cells.

Leinamycin is a structurally novel Streptomyces-derived natural product that displays very potent activity against various human cancer cell lines (IC(50) values in the low nanomolar range). Previous in vitro biochemical studies have revealed that leinamycin alkylates DNA, generates apurinic (AP) sites and reactive oxygen species (ROS), and causes DNA strand breaks. However, it is not clear whether these events occur inside cells. In the present study, we have determined the endogenous amount of AP sites and DNA strand breaks in genomic DNA and the amount of oxidative stress in a human pancreatic carcinoma cell line, MiaPaCa, treated with leinamycin by utilizing the aldehyde-reactive probe assay, the comet assay, and fluorescent probes, respectively. We demonstrated that AP sites are formed rapidly following exposure to leinamycin, and the number of AP sites was increased up to seven-fold in a dose-dependent manner. However, only 25-50% of these sites remain 2 h after media containing drug molecules were aspirated and replaced with fresh media. We also observed leinamycin-induced ROS generation and a concomitant increase in apoptosis of MiaPaCa cells. Because both AP sites and ROS have the potential to generate strand breaks in cellular DNA, the comet assay was utilized to detect damage to nuclear DNA in leinamycin-treated MiaPaCa cell cultures. Both alkaline and neutral electrophoretic analysis revealed that leinamycin produces both single- and double-stranded DNA damage in drug-treated cells in a dose-dependent manner. Taken together, the results suggest that rapid conversion of leinamycin-guanine (N7) adducts into AP sites to produce DNA strand breaks, in synergy with leinamycin-derived ROS, accounts for the exceedingly potent biological activity of this natural product.