Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs).

Although targeting TfR1 to deliver oligonucleotides to skeletal muscle has been demonstrated in rodents, effectiveness and pharmacokinetic/pharmacodynamic (PKPD) properties remained unknown in higher species. We developed antibody-oligonucleotide conjugates (AOCs) towards mice or monkeys utilizing anti-TfR1 monoclonal antibodies (αTfR1) conjugated to various classes of oligonucleotides (siRNA, ASOs and PMOs). αTfR1 AOCs delivered oligonucleotides to muscle tissue in both species. In mice, αTfR1 AOCs achieved a > 15-fold higher concentration to muscle tissue than unconjugated siRNA. A single dose of an αTfR1 conjugated to an siRNA against Ssb mRNA produced > 75% Ssb mRNA reduction in mice and monkeys, and mRNA silencing was greatest in skeletal and cardiac (striated) muscle with minimal to no activity in other major organs. In mice the EC50 for Ssb mRNA reduction in skeletal muscle was >75-fold less than in systemic tissues. Oligonucleotides conjugated to control antibodies or cholesterol produced no mRNA reduction or were 10-fold less potent, respectively. Tissue PKPD of AOCs demonstrated mRNA silencing activity primarily driven by receptor-mediated delivery in striated muscle for siRNA oligonucleotides. In mice, we show that AOC-mediated delivery is operable across various oligonucleotide modalities. AOC PKPD properties translated to higher species, providing promise for a new class of oligonucleotide therapeutics.

Comparing the cardiorespiratory safety of parenteral olanzapine and benzodiazepines to parenteral haloperidol/droperidol and benzodiazepines in emergency department patients.

INTRODUCTION: This study sought to assess the cardiorespiratory safety of parenteral olanzapine and benzodiazepine combination treatment compared to parenteral droperidol or haloperidol and benzodiazepine combination treatment. MATERIALS AND METHODS: This was a retrospective chart review conducted in adult emergency department patients who received intramuscular (IM) or intravenous (IV) droperidol, haloperidol, or olanzapine within one hour of IM or IV benzodiazepine. Patients were stratified into groups based on whether they received either olanzapine in combination with a benzodiazepine (n = 48) or droperidol or haloperidol in combination with a benzodiazepine (n = 48). RESULTS: Patients in each group had a decrease in their systolic blood pressure (SBP) after IM/IV olanzapine and IM/IV droperidol or haloperidol when used in combination with an IM/IV benzodiazepine ((Olanzapine + benzodiazepine (mmHg), median (IQR): Pre-SBP: 132 (117-151) vs. Post-SBP: 117 (99-131), p < 0.01) (Droperidol or haloperidol + benzodiazepine (mmHg), median (IQR): Pre-SBP: 138 (122-149) vs. Post-SBP: 106 (98-127), p < 0.01)). Both groups had similar percent SBP decreases post-combination treatment (Olanzapine + benzodiazepine (15.6 %) vs. Droperidol or haloperidol + benzodiazepine (15.2 %); p = 0.55). We did not observe any statistically significant between group differences for hypotension (Olanzapine + benzodiazepine: 1/48, 2.1 % vs. Droperidol or haloperidol + benzodiazepine: 3/48, 6.3 %; p = 0.62)), escalation in oxygen requirements (Olanzapine + benzodiazepine: 7/48, 14.6 %) vs. Droperidol or haloperidol + benzodiazepine: 5/48, 10.4 %; p = 0.76)), or intubation due to cardiorespiratory depression (Olanzapine + benzodiazepine: 0/0, 0 % vs. Droperidol or haloperidol + benzodiazepine: 0/0, 0 %; p = 1.00)). CONCLUSION: This study found decreases in SBP after administering parenteral olanzapine and parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine. The percent change in SBP and the frequency of hypotensive episodes post-combination treatment were not different between groups. There were also no differences between groups in need of increased oxygen requirements post-combination treatment or need for intubation due to cardiorespiratory depression. This study suggests parenteral olanzapine in combination with a parenteral benzodiazepine may have comparable cardiorespiratory safety versus parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine when treating agitation in the adult ED.

Accuracy of 4 Free Online Dosing Calculators in Predicting the Vancomycin Area Under the Concentration-Time Curve Calculated Using a 2-Point Pharmacokinetic Approach.

BACKGROUND: Free online adaptive vancomycin dosing calculators are available to estimate area under the concentration-time curve (AUC), but the accuracy of predicting vancomycin AUC using these calculators compared with using a 2-point pharmacokinetic approach has not been described. OBJECTIVE: To evaluate the accuracy of calculator-predicted AUC (cpAUC) using 4 free online calculators compared with reference AUC (rAUC), and to assess pharmacists' impressions of the ease of use. METHODS: Vancomycin AUC was estimated using (1) the reference method via the Sawchuk-Zaske method and linear-logarithmic trapezoidal rule using 2 steady-state postdistributional vancomycin serum concentrations and (2) 4 free online vancomycin dosing calculators including ClinCalc, VancoPK, TDMx, and DMC. Accuracy was calculated by dividing cpAUC by rAUC. Ease of cpAUC estimation was determined by using a 10-point Likert scale. RESULTS: All 4 calculators had a median cpAUC accuracy ranging from 89% to 110%. Concordance between cpAUC and rAUC determinations of AUC <400 and > 600 mg·h/L occurred 63.3% to 71.4% and 74.5% to 78.6% of the time, respectively. Pharmacist investigators agreed that ClinCalc and VancoPK calculators were easiest to use. CONCLUSION AND RELEVANCE: cpAUC accuracy varied among the 4 calculators, but all consistently identified patients with an rAUC <400 mg·h/L and an rAUC > 600 mg·h/L at comparable frequencies. All 4 calculators demonstrated some imprecision based on their wide 95% CIs and potential inaccuracies in predicting an rAUC <400 mg·h/L or an rAUC > 600 mg·h/L. Clin Calc and VancoPK were most user friendly based on our pharmacists' impressions.

Does a Positive Methicillin-Resistant Staphylococcus aureus (MRSA) Nasal Screen Predict the Risk for MRSA Skin and Soft Tissue Infection?

BACKGROUND: Skin and soft tissue infections (SSTIs) are often caused by gram-positive bacteria that colonize the skin. Given the overuse of antibiotics, SSTIs are increasingly caused by resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Guidance on the utility of MRSA nasal screening for MRSA SSTI is limited. OBJECTIVE: To determine whether MRSA nasal screening predicts the risk of MRSA SSTIs. METHODS: This was a single-center, retrospective cohort study of adult patients with an SSTI diagnosis that had MRSA nasal screening and wound cultures obtained within 48 hours of starting antibiotics. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated using VassarStats. Pretest and posttest probabilities were estimated with Microsoft Excel. RESULTS: A total of 884 patient encounters were reviewed between December 1, 2018, and October 31, 2021, and 300 patient encounters were included. The prevalence of MRSA SSTI was 18.3%. The MRSA nasal colonization had a sensitivity of 63.6%, specificity of 93.9%, positive predictive value of 70.0% (95% CI = 55.2%-81.7%), negative predictive value of 92.0% (95% CI = 87.7%-94.9%), positive likelihood ratio of 10.39 (95% CI = 6.12-17.65), negative likelihood ratio of 0.39 (95% CI = 0.27-0.55), positive posttest probability of 70.0%, and negative posttest probability of 8.0%. CONCLUSIONS: Given the high positive likelihood ratio, a positive MRSA nasal screen was associated with a large increase in the probability of MRSA SSTI at our institution, and a negative MRSA nasal screen was associated with a small but potentially significant decrease in the probability of MRSA SSTI.

Hospital Discharge: An Opportune Time for Antimicrobial Stewardship.

BACKGROUND: Approximately 30% of antimicrobials prescribed in the outpatient setting are unnecessary and up to 50% are inappropriate. Despite this, antimicrobial stewardship (AS) efforts mostly focus on the inpatient setting, and limited data describe AS interventions at hospital discharge. Acknowledging the potential value of discharge AS, we used our existing resources to review discharge oral antimicrobial prescriptions. OBJECTIVE: The primary objective of this retrospective, single-center study was to evaluate the impact of an AS program on discharge oral antimicrobial prescriptions. METHODS: Discharge oral antimicrobial prescriptions sent to our hospital-operated outpatient pharmacy, reviewed by an infectious diseases (ID) pharmacist, and recorded into our data collection tool from September 1, 2020, to February 28, 2021, were evaluated retrospectively. The primary outcome was to identify the frequency a drug-related problem (DRP) was identified by an ID pharmacist. Secondary outcomes included DRP characterization, percentage of prescriptions with interventions, intervention acceptance rate, and reduction in antimicrobial days dispensed at discharge when interventions to limit treatment duration were accepted. RESULTS: Of the 803 discharge oral antimicrobial prescriptions reviewed, at least 1 DRP was identified in 43.1% (346/803). The most frequently identified DRPs pertained to treatment duration, drug selection, and dose selection. At least 1 intervention was recommended in 42.8% (344/803) of prescriptions. In total, 438 interventions were made and the acceptance rate was 75.6% (331/438). The most common types of interventions included recommendations for a different duration, a different dose or frequency, and antimicrobial discontinuation. When interventions to reduce treatment duration were accepted, the median (interquartile range) number of antimicrobial days decreased from 8 (5-10) days to 4 (0-5.5) days (P < 0.001). CONCLUSION AND RELEVANCE: An ID pharmacist's review of discharge oral antimicrobial prescriptions sent to our hospital-operated outpatient pharmacy resulted in identification of DRPs and subsequent interventions in a substantial number of prescriptions.

Andexanet alfa effectiveness and safety versus four-factor prothrombin complex concentrate (4F-PCC) in intracranial hemorrhage while on apixaban or rivaroxaban: A single-center, retrospective, matched cohort analysis.

BACKGROUND: There is limited information directly comparing andexanet alfa (AA) versus four-factor prothrombin complex concentrate (4F-PCC) in intracranial hemorrhage (ICH) on apixaban or rivaroxaban. OBJECTIVE: The objective of this study was to compare the effectiveness and safety of AA versus 4F-PCC in ICH on apixaban or rivaroxaban. METHODS: This retrospective, matched, cohort analysis was conducted at a single healthcare system. Patients were matched based on baseline ICH volume. The primary outcome was good or excellent ICH hemostasis, which was defined as a 35% or less increase in ICH volume within 24 h following AA or 4F-PCC administration. The secondary outcome was thrombotic events within 14 days following AA or 4F-PCC administration. RESULTS: In total, 26 AA and 26 4F-PCC patients were included in this matched cohort analysis. Both groups had comparable rates of good or excellent ICH hemostasis (AA: 92.3% vs. 4F-PCC: 88.5%, p = 1.000). Thrombotic events within 14-days were not significantly different (AA: 26.9% vs. 4F-PCC: 11.5%, p = 0.159). CONCLUSION AND RELEVANCE: This study found no significant differences in good or excellent ICH hemostasis within 24-h or new thrombotic events within 14-days in a cohort given AA or 4F-PCC for ICH while on apixaban or rivaroxaban. However, this single-center analysis is underpowered due to sample size constraints, therefore further high-quality research comparing AA safety and effectiveness versus 4F-PCC is needed.

Comparison of vancomycin area under the concentration-time curve (AUC) using two-point pharmacokinetics versus two open-access online single-concentration vancomycin calculators.

WHAT IS KNOWN AND OBJECTIVE: Current vancomycin monitoring guidelines recommend the use of area under the concentration-time curve (AUC24 ) monitoring in patients with serious Methicillin-Resistant Staphylococcus aureus (MRSA) infections by utilizing either a Bayesian approach or first-order analytic equations. Several open-access websites exist that allow estimation of vancomycin AUC24 with the use of a single steady-state concentration. It is uncertain how these open-access calculators perform against guideline-recommended methods. The objective was to compare AUC24 estimates from two online, open-access, single-concentration vancomycin calculators compared with the two-point pharmacokinetic (2PK) method. METHODS: AUC24 estimates were made using the 2PK reference method and the single-concentration vancomycin calculators, ClinCalc and VancoPK. The AUC24 estimates from the 2PK reference method were compared to the online calculators by assessing bias (median AUC24 difference) and precision (AUC24 difference ± 100 mg*h/L). Clinical precision was also assessed by characterizing the frequency that the 2PK reference method and the online calculators showed clinical disagreement based on the following AUC24 categories: (1) AUC24 < 400 mg*h/L; (2) AUC24 400-600 mg*h/L and (3) AUC24 > 600 mg*h/L. RESULTS AND DISCUSSION: A total of 253 patients were included in the study. The AUC24 estimates from the ClinCalc and VancoPK single-concentration vancomycin calculators showed some bias and imprecision, though VancoPK appeared to have less. Clinical disagreement versus the 2PK reference method occurred in 31.2% and 19.4% of AUC24 estimates from the ClinCalc and VancoPK single-concentration vancomycin calculators, suggesting clinical imprecision. WHAT IS NEW AND CONCLUSION: The AUC24 estimates from single-concentration, online vancomycin calculators showed some bias and imprecision in comparison to the 2PK method. Institutions should validate these online, trough-only calculators relative to a 2PK method in their patient populations prior to adoption as standard-of-care.

Prophylactic Enoxaparin in Critically Ill Trauma Patients: Evaluation of the Initial Dose.

Background: Trauma patients are at increased risk of developing venous thromboembolism given alterations in the coagulation cascade. Chemoprophylaxis with standard dosing of enoxaparin 30 mg subcutaneously twice daily has evolved to incorporate the use of anti-factor Xa (AFXa) trough level monitoring given concerns for decreased enoxaparin bioavailability in this patient population. Current available evidence suggests low rates of goal AFXa trough level achievement with standard enoxaparin dosing. Our study aims to identify the incidence of critically ill trauma patients that did not achieve goal AFXa trough levels and attempts to identify predictors that may influence the lack of achievement of goal levels. Methods: This was a retrospective, cohort analysis performed at a single academic medical center. Adult patients 18 years or older admitted to the surgical intensive care unit secondary to trauma who were initiated on standard prophylactic enoxaparin and had at least 1 AFXa trough level representative of steady state were included. Patient demographics and clinical data were collected, and descriptive statistics were utilized. All statistical tests were 2-tailed and a P < .05 was considered significant. Variables with a P < .10 on univariable analysis were included in a multivariable logistic regression analysis. Results: A majority of our patient population did not achieve goal AFXa trough levels while receiving standard doses of prophylactic enoxaparin (82.4% [108/131]). Sub-target AFXa levels were associated with higher creatinine clearance values. Positive predictors of obtaining target AFXa levels included automobile versus pedestrian mechanism of injury and requiring an enoxaparin dose escalation to at least 40 mg twice daily. Conclusions: Our study found low rates of achievement of goal AFXa trough levels in critically ill trauma patients receiving standard prophylactic enoxaparin dosing. Certain variables were identified as negative and positive predictors for achievement of goal AFXa trough levels, although the biologic plausibility of these predictors is questionable and requires further investigation.

Validation of Methicillin-Resistant Staphylococcus aureus (MRSA) Risk Factors in Predicting MRSA Community-Acquired Pneumonia at an Academic Medical Center.

Background: The 2019 Infectious Diseases Society of America community-acquired pneumonia (CAP) guidelines recommend antimethicillin- resistant Staphylococcus aureus (MRSA) therapy in patients with CAP based on previously identified risk factors for MRSA with an emphasis on local epidemiology and institutional validation of risk. Thus, we sought to assess the ability of guideline-recognized risk factors to predict MRSA CAP at our institution. Methods: This was a single-center, retrospective cohort study from January 2016 to March 2020. Patients were included if they were >18 years old, diagnosed with CAP, and had a MRSA nasal screen and respiratory culture obtained on admission. Patients were excluded if CAP diagnosis was not met, respiratory cultures were not obtained within 48 hours of antibiotic initiation, or they had cystic fibrosis. Sensitivity, specificity, negative predictive value, positive predictive value, and likelihood ratios (LR) were calculated using Vasser Stats 2019. Pre/post-test odds and pre/post-test probabilities were calculated using Excel 2019. Results: Of 705 screened patients, 221 were included. MRSA prevalence in CAP patients at our institution was 3.6%. History of MRSA isolated from a respiratory specimen had high specificity (98%), high positive LR of 20 (95% CI 5.3-74.8), and high post-test probability of 42.8%. Receipt of IV antibiotics during hospitalization within the past 90 days had a positive LR of 1.9 (95% CI 0.74-4.84). A positive MRSA nasal screen on admission had a positive LR of 6.9 (95% CI 4.0-12.1), negative LR 0.28 (95% CI 0.08-0.93), positive post-test probability of 20.7%, and negative post-test probability of 1.04%. Conclusion: Our study utilized institutional data to validate guideline recognized risk factors for MRSA CAP specifically at our institution. Risk factors including history of MRSA isolated from a respiratory specimen, and positive post-admission MRSA nasal screen were validated as significant risk factors; receipt of IV antibiotics during hospitalization within the past 90 days was not shown to be a risk factor for MRSA CAP based on our institutional data. Validated risk factors may help providers discern which patients with CAP at our institution would benefit most from empiric MRSA treatment.

Chemical and Physical Stability of an Admixture Containing Cefepime and Vancomycin in Lactated Ringer Solution.

Purpose: To evaluate the chemical and physical stability of an admixture containing cefepime and vancomycin in a single volume of lactated Ringer solution at refrigerated temperatures. Methods: Cefepime 2000 mg and vancomycin 1000 mg were, respectively, reconstituted with 10 and 20 mL of sterile water for injection (SWFI) per manufacturer instructions. This resulted in cefepime and vancomycin concentrations of 200 and 50 mg/mL, respectively. The resulting cefepime and vancomycin solutions at 10 and 20 mL, respectively, were drawn up and injected into 1000 mL lactated Ringer solution. Aliquot samples were obtained on days 0 to 9, visually inspected for gross incompatibility, and then stored at -80°C. Samples were thawed on the day of the analysis and run through ultraperformance liquid chromatography. Area under the concentration-time curve (AUC) on each day was compared with baseline AUC values. Chemical stability was defined as an AUC more than 93% of the baseline value. Results: No evidence of gross physical incompatibility was observed by visual inspection. Cefepime and vancomycin replicants were more than 94.5% and 98% of baseline AUC values. Therefore, all sample replicants were found to be more than 93% of their baseline AUC value. Conclusion: An admixture containing cefepime 2000 mg and vancomycin 1000 mg in 1000 mL lactated Ringer solution appears to be chemically and physically stable at refrigerated temperatures for up to 9 days.

Cost comparison of AUC:MIC- versus trough-based vancomycin monitoring for MRSA bacteremia.

OBJECTIVES: It is anticipated that the updated vancomycin monitoring guidelines will reconsider area under the concentration-time curve to minimum inhibitory concentration ratio (AUC:MIC)-based monitoring instead of trough-based monitoring for methicillin-resistant Staphylococcus aureus (MRSA) infections. The AUC:MIC can be estimated using 2 steady-state serum concentrations and first-order pharmacokinetic equations or Bayesian modeling. The cost of AUC:MIC-based monitoring compared with trough-based monitoring is unknown and has been cited as a potential barrier to implementing this monitoring method. The objective of this study was to compare the total vancomycin drug and monitoring cost for patients with MRSA bacteremia who received AUC:MIC- or trough-based monitoring. DESIGN: This was a single-center, retrospective cohort study. SETTING AND PARTICIPANTS: This study included patients who were treated for MRSA bacteremia between May 1, 2013 and December 31, 2018, with an 8-month washout period between trough and AUC:MIC-based monitoring at our institution. OUTCOME MEASURES: The primary outcome was the aggregate cost of vancomycin therapy, which included the cost associated with sample collection (i.e., supply cost and nursing time), sample analysis (i.e., assay cost and laboratory technician time), result interpretation (i.e., pharmacist time), and drug cost (i.e., cost of total administered vancomycin dose) during the hospital stay. RESULTS: A total of 52 patients met inclusion criteria with 26 patients in each group. The median (interquartile range) total vancomycin drug and monitoring cost was $338.14 ($235.07-$601.05) for the AUC:MIC-based group compared with $316.79 ($253.36-$520.96) for the trough-based group (P = 0.687). CONCLUSION: Vancomycin monitoring using 2 steady-state serum concentrations and first-order pharmacokinetic equations to calculate AUC:MIC was no more costly than a trough-based approach in patients with MRSA bacteremia at our institution.

Effect of a Standardized Treatment Panel on Hypoglycemic Events in Hospitalized Acute Hyperkalemic Patients Treated With Intravenous Regular Insulin.

Purpose: Regular insulin is a commonly utilized treatment option for acute hyperkalemia. Despite its benefit, hypoglycemia and associated morbidity/mortality remain important concerns. This institution recently created a treatment panel to standardize regular insulin dosing (0.1 unit/kg) and blood glucose (BG) monitoring in patients with acute hyperkalemia. The purpose of this study is to investigate whether the order panel reduces hypoglycemic events in adults treated with intravenous (IV) regular insulin for hyperkalemia and to determine the effect the treatment panel has on regular insulin dosing, serum potassium, BG monitoring, and dextrose supplementation. Methods: This retrospective study was performed at a single academic medical center. Adults receiving IV regular insulin for acute hyperkalemia were included if BG was assessed prior to and following regular insulin administration. Primary outcome was hypoglycemia within 4 hours of regular insulin administration. Secondary outcomes were the change from baseline serum potassium, frequency of severe hypoglycemia, BG checks within 30 minutes prior to and within 4 hours following insulin administration, regular insulin dosing, and administration of dextrose 50% in water (D50W) following regular insulin administration. Hypoglycemia and severe hypoglycemia were defined as a BG concentration of <70 mg/dL and <50 mg/dL, respectively. Results: One hundred sixty-five patients were included; 75 using the treatment panel and 90 not. Patients using the treatment panel received a lower median (interquartile range [IQR]) regular insulin dose (.10 [0.09-0.10 unit/kg] vs 0.11 [0.09-0.14 unit/kg], P = .004) and had more frequent BG checks during the 4 hours following regular insulin administration (median [IQR]: 4 [3-5] vs 2 [1-3], P < .001). Hypoglycemia (13.3% vs 27.8%, P = .024) and severe hypoglycemia (2.7% vs 11.1%, P = .038) occurred less frequently with the treatment panel. Similar decreases in serum potassium were noted following IV regular insulin administration. Conclusions: Acute hyperkalemic patients utilizing a standardized treatment panel for the dosing and monitoring of IV regular insulin experienced fewer hypoglycemic and severe hypoglycemic episodes and had similar potassium lower effects. The treatment panel decreased regular insulin dosing and increased BG monitoring prior to and following regular insulin administration.

Evaluation of a Long-Acting Opioid Restriction Policy: Does Restriction Reduce the Need for Naloxone Reversal?

Purpose: After a sentinel event related to long-acting (LA) opioid administration at our institution and subsequent root cause analysis, an inpatient LA opioid restriction policy was implemented to improve patient safety. The objectives of this study were to evaluate the effect of an inpatient LA opioid restriction policy on inpatient therapy utilization and to compare rates of naloxone reversal events among patients administered LA opioids before and after policy implementation. Methods: To evaluate the first objective, an electronic medical record report was created to capture all inpatient LA opioid orders prescribed to adults at our institution between March 1, 2014, and July 30, 2017. Utilization was compared before and after policy implementation and use controlled for by patient days. To evaluate the second objective, naloxone administrations were identified via a query of the medical record between March 1, 2014, and July 30, 2017. Naloxone reversal events were independently evaluated by 2 trained reviewers, and a third when discrepancies existed. Rates of naloxone reversal events related to LA opioid administration were compared between the pre- and post-policy phase. Results: The results of our first objective demonstrate that policy implementation was associated with a statistically significant reduction in LA opioid utilization that was sustained throughout the study duration. For our second objective, among the 144 patients deemed to have an opioid-related naloxone reversal event, a LA opioid was administered to 12 patients (18.9%) in the pre-policy phase and 17 patients (15.9%) in the post-policy phase. This difference was not statistically significant (odds ratio [OR] = 1.629, confidence interval [CI] = 0.711-3.732, P = .248). Conclusion: A LA opioid restriction policy significantly reduced LA opioid utilization at our institution. Despite this, we did not find a significant reduction in inpatient naloxone reversals related to LA opioids. Further study is warranted to identify an optimal method to reduce LA opioid-related toxicity.

Retrospective Assessment of Desmopressin Effectiveness and Safety in Patients With Antiplatelet-Associated Intracranial Hemorrhage.

OBJECTIVE: Current international guidelines offer a conditional recommendation to consider a single dose of IV desmopressin (DDAVP) for antiplatelet-associated intracranial hemorrhage based on low-quality evidence. We provide the first comparative assessment analyzing DDAVP effectiveness and safety in antiplatelet-associated intracranial hemorrhage. DESIGN: Retrospective chart review. SETTING: Single tertiary care academic medical center. PATIENTS: Adult patients taking at least one antiplatelet agent based on presenting history and documented evidence of intracranial hemorrhage on cerebral CT scan were included. Patients were excluded for the following reasons: repeat cerebral CT scan not performed within the first 24 hours, noncomparative repeat cerebral CT scan, chronic anticoagulation, administration of fibrinolytic medications, concurrent ischemic stroke, and neurosurgical intervention. In total, 124 patients were included, 55 received DDAVP and 69 did not. INTERVENTIONS: DDAVP treatment at recognition of antiplatelet-associated intracranial hemorrhage versus nontreatment. MEASUREMENTS AND MAIN RESULTS: Primary effectiveness outcome was intracranial hemorrhage expansion greater than or equal to 3 mL during the first 24 hospital hours. Primary safety outcomes were the largest absolute decrease from baseline serum sodium during the first 3 treatment days and new-onset thrombotic events during the first 7 days. DDAVP was associated with 88% decreased likelihood of intracranial hemorrhage expansion during the first 24 hours ([+] DDAVP, 10.9% vs [-] DDAVP, 36.2%; p = 0.002; odds ratio [95% CI], 0.22 [0.08-0.57]). Largest median absolute decrease from baseline serum sodium ([+] DDAVP, 0 mEq/L [0-5 mEq/L] vs [-] DDAVP, 0 mEq/L [0-2 mEq/L]; p = 0.089) and thrombotic events ([+] DDAVP, 7.3% vs [-] DDAVP, 1.4%; p = 0.170; odds ratio [95% CI], 5.33 [0.58-49.16]) were similar between groups. CONCLUSIONS: DDAVP was associated with a decreased likelihood of intracranial hemorrhage expansion during the first 24 hours. DDAVP administration did not significantly affect serum sodium and thrombotic events during the study period.

The Culture of Carbapenem Overconsumption: Where Does It Begin? Results of a Single-Center Survey.

Purpose: The United States has seen an increased consumption of carbapenem antibiotics in recent years. The increased utilization of these agents has potential negative consequences, including the increasing incidence of carbapenem-resistant Enterobacteriaceae. Reasons for the rise in carbapenem use among providers in acute care hospitals are not well elucidated in literature. The objectives of this study were to identify factors that influence empiric carbapenem use among providers in a single academic medical center, and to assess therapeutic knowledge pertaining to carbapenem use. Methods: A cross-sectional, single-center, 9-item electronic research survey was developed independently and validated by an infectious diseases pharmacist and infectious diseases physician. The survey was distributed to email accounts of providers at a single academic medical center. Demographic data, factors affecting carbapenem prescription, and baseline therapeutic knowledge were assessed. Results: Ninety-five of 416 providers responded to the survey (response rate of 22.8%). Respondents were well distributed across all levels of training with primary roles in internal medicine and surgery. The most important factors influencing empiric carbapenem use were suspected pathogens at the site of infection, drug allergies, history of multidrug resistant organisms, severity of illness, type of infection, and local resistance rates. A recommendation from a pharmacist was selected as the most likely factor for deterring carbapenem use. Misconceptions pertaining to penicillin drug allergy and beta-lactam cross reactivity, knowledge of local resistance rates according to the institutional antibiogram, and comparative efficacy data for carbapenems were apparent across all levels of training. Conclusions: Provider misconceptions regarding several factors appear to contribute to unnecessary use of carbapenems. An opportunity exists for hospital pharmacists to improve the prescribing patterns of carbapenems by correcting provider misconceptions through education.

Accessing Ambiphilic Phosphine Boronates through C-H Borylation by an Unforeseen Cationic Iridium Complex.

Ambiphilic molecules, which contain a Lewis base and Lewis acid, are of great interest based on their unique ability to activate small molecules. Phosphine boronates are one class of these substrates that have interesting catalytic activity. Direct access to these phosphine boronates is described through the iridium-catalyzed C-H borylation of phosphines. An unconventional cationic iridium catalyst was identified as optimal for a range of phosphines, providing good yields and selectivity across a diverse class of phosphine boronates (isolated as the borane-protected phosphine). A complimentary catalyst system (quinoline-based silane ligand with [(COD)IrOMe]2 ) was optimal for biphenyl-based phosphines. Selective polyborylation was also shown providing bis- and tris-borylated phosphines. Deprotection of the phosphine boronate provided free ambiphilic phosphine boronates, which do not have detectable interactions between the phosphorus and boron atoms in solution or the solid state.

Impact of a Combination Antibiotic Bag on Compliance With Surviving Sepsis Campaign Goals in Emergency Department Patients With Severe Sepsis and Septic Shock.

BACKGROUND: Severe sepsis and septic shock represent common presentations in the emergency department (ED) and have high rates of mortality. Guideline-recommended goals of care have been shown to benefit these patients, but can be difficult to provide. OBJECTIVE: To determine whether the use of a premixed bag consisting of 2 g cefepime and 1 g vancomycin in 1000 mL of normal saline increases the probability of patients receiving Surviving Sepsis Campaign (SSC) recommendations for the initiation of antimicrobials and fluid challenge. METHODS: This was a 6-month retrospective analysis conducted to determine the impact of an intervention on time to antimicrobials and fluid administration in patients with severe sepsis and septic shock. Patients presenting to the ED who received a diagnosis of severe sepsis or septic shock and were administered 2 antibiotics were eligible for inclusion. The primary outcome assessed was compliance with SSC recommendations for antibiotic and fluid goals within 3 hours of ED arrival. RESULTS: A total of 160 patients were included. In the intervention group, 63.8% of patients met the primary outcome compared with 22.5% in the historical group (odds ratio = 2.32; 95% CI = 1.67-3.23). Time to administration of antibiotics was less with the combination antibiotic bag (CAB: median (IQR) = 72 (48-115) minutes; non-CAB: median (IQR) = 135 (102-244) minutes; P ≤ 0.001). CONCLUSION: This intervention significantly increased the proportion of patients provided with SSC goals of care. Such interventions have not been reported previously and could be meaningful in the management of severe sepsis and septic shock.

Changes in Pharmacy Residency Training Design Between 2012 and 2017: A Perspective of Academic Medical Centers.

Purpose:The role of health-system pharmacists continues to expand, and this area of pharmacy practice increasingly requires augmented baseline training. It is unclear how Post Graduate Year 1 (PGY-1) pharmacy residencies may be changing to meet these needs.The objectives of our survey were to describe PGY-1 pharmacy residency program design among academic medical centers, characterize program changes enacted over 5-year period, and describe career paths among PGY-1 pharmacy residency graduates. Methods: A 32-item questionnaire was developed independently, which was reviewed and validated by 4 residency program directors. The survey was uploaded to an online survey tool and sent electronically to residency program directors of 109 Vizient academic medical centers with PGY-1 pharmacy residency programs. Residency program directors were identified from a list of Vizient-participating hospitals. The survey was re-sent at 2-week intervals on 4 occasions to improve response rates. SPSS version 23.0 was used to analyze the data. Results: Overall, 49 (45%) of hospitals responded to the survey. Survey responses showed statistically significant increases over the 5-year survey period in the following areas: the number of PGY-1 resident positions offered (P = .001), percent of time spent on teaching experiences (P = .001), and percentage of PGY-1 residents pursuing PGY-2 or fellowship training (P = .026). Conclusion: We found that PGY-1 pharmacy residency programs at Vizient academic medical centers have undergone limited changes over the 5-year survey period and substantial variation exists between program designs. The most common change to program design was an increase in the percentage of time residents spend on teaching experiences. There was an increase in residents pursuing PGY-2 or fellowship training, which may suggest a shift toward increased specialization in clinical pharmacy practice or may reflect changes in the availability of job opportunities.

Clinical Feasibility of Monitoring Enoxaparin Anti-Xa Concentrations: Are We Getting It Right?

Background: Anti-Xa monitoring is utilized to measure the extent of anticoagulation in certain patient populations receiving enoxaparin. It is essential to accurately obtain this pharmacodynamic marker for safe and effective anticoagulation management. Objectives: To determine the frequency of correctly drawn anti-Xa concentrations in accordance with predefined institutional criteria and to determine the number of dose adjustments implemented based on incorrectly drawn anti-Xa concentrations. Methods: This was a retrospective, single-center, cohort study among adult patients who received treatment doses of enoxaparin with measured anti-Xa concentrations. Patients were excluded if they were pregnant, on hemodialysis, or received prophylactic dosing. Anti-Xa levels were defined as correctly measured if they were drawn 3 to 5 hours after the dose during steady state concentrations. Descriptive statistics were performed and analyzed via SPSS software. Results: Overall, 203 patients were reviewed and 59 patients with 74 anti-Xa levels were included. The majority of anti-Xa levels (57/74; 77%) were drawn incorrectly and often resulted in collection of repeat anti-Xa samples. There were 12 documented dose adjustments and approximately 42% (5/12) were based on incorrectly drawn anti-Xa levels. Anti-Xa levels were within target range approximately 45% of the time. Conclusions: Enoxaparin anti-Xa concentrations are frequently drawn incorrectly and dose adjustments are often performed based on these unsupported anti-Xa levels. This may present a potential risk to compromise patient safety.

Y-site Incompatibility Between Premix Concentrations of Vancomycin and Piperacillin-Tazobactam: Do Current Compatibility Testing Methodologies Tell the Whole Story?

Background: Published literature has demonstrated commercially available premix vancomycin (5 mg/mL) and piperacillin-tazobactam (67.5 mg/mL) as physically compatible via simulated Y-site methodology. Compatibility via actual Y-site infusion has yet to be established. Objective: To assess and compare the compatibility of commercially available premix concentrations of vancomycin and piperacillin-tazobactam via simulated and actual Y-site evaluation. Methods: Vancomycin and piperacillin-tazobactam were tested using simulated and actual Y-site infusion methodologies. Simulated Y-site compatibility was performed using previously published methods via visual inspection, turbidity evaluation, and pH evaluation. Evaluation occurred immediately, 60 minutes, 120 minutes, and 240 minutes following mixing for each mixture and control. Mixtures were considered physically incompatible if there was visual evidence of precipitation or haze, an absorbance value was greater than 0.01 A, or an absolute change of 1.0 pH unit occurred. Actual Y-site infusion was simulated to mirror antibiotic infusion in the clinical setting by nursing personnel using smart pumps and intravenous tubing. Results: No evidence of physical incompatibility was observed during simulated Y-site testing via visual inspection, turbidity assessment, and pH evaluation. Conversely, physical incompatibility was observed to the unaided eye within 2 minutes during actual Y-site infusion. Conclusions: Despite observed compatibility between vancomycin and piperacillin-tazobactam via simulated Y-site testing, visual evidence of physical incompatibility was observed during actual Y-site infusion. This poses a potential compromise to patient safety if these antibiotics are administered simultaneously in the clinical setting. Actual Y-site testing should be performed prior to clinical adoption of compatibility studies that are based solely on simulated methodologies.