Predictors of Treatment Failure Following De-escalation to a Fluoroquinolone in Culture-Negative Nosocomial Pneumonia.

Background: Little evidence exists for de-escalation of nosocomial pneumonia therapy without positive cultures. Objective: The purpose of this study was to identify potential predictors of treatment failure following de-escalation to a fluoroquinolone in culture-negative nosocomial pneumonia. Methods: The study involved a single-center, retrospective cohort of patients admitted with diagnosis of nosocomial pneumonia and positive chest radiography who received at least 24 hours of fluoroquinolone monotherapy following at least 24 hours of appropriate empirical antibiotics. Treatment failure was defined using a composite of all-cause death within 30 days of discharge, treatment re-escalation, or readmission for pneumonia within 30 days of discharge. The Cox proportional hazards model was used to analyze predictors of treatment failure. Duration of empirical antibiotics and significant univariable exploratory predictors were included in multivariable analysis. Results: Of 164 patients, 23 (14%) failed de-escalation. Duration of empirical antibiotics (68.5 ± 32.1 vs 65.8 ± 35 hours) was not associated with treatment failure in univariable (Hazard Ratio [HR] = 1.002 [95% CI = 0.991-1.013]) or multivariable analyses (HR = 1.003 [95% CI = 0.991-1.015]). Significant exploratory predictors on univariable analysis included active cancer, intensive care unit (ICU) admission at empirical initiation, APACHE II score, and steroid use ≥20-mg prednisone equivalent. ICU admission at empirical initiation (HR = 2.439 [95% CI = 1.048-5.676]) and steroid use ≥20-mg prednisone equivalent (HR = 2.946 [95% CI = 1.281-6.772]) were associated with treatment failure on multivariable analysis. Conclusion and Relevance: Duration of empirical antibiotics does not appear to influence failure of de-escalation to fluoroquinolone monotherapy in culture-negative nosocomial pneumonia.

The Importance of Research and Scholarly Activity in Pharmacy Training.

Regardless of practice setting, it is imperative that pharmacists be able to either participate in generating new knowledge or use the ever-expanding body of literature to guide patient care. However, competing priorities in Pharm.D. curricula and residency training programs have resulted in limited emphasis on acquiring research and scholarly skills. Factors likely contributing to this reduced focus include the lack of curricular and postgraduate training standards emphasizing the development of research skills, time to commit to scholarly activity, and accessibility to experienced mentors. Strategies for increasing scholarly activity for pharmacy students and residents should therefore continue to be a focus of professional degree and residency training programs. Several resources are available for academic planners, program directors, and institutions to augment scholarly experience for pharmacy trainees and clinicians. This commentary highlights the importance of providing research opportunities for students and residents, describes the potential barriers to these activities, and provides recommendations on how to increase the instruction and mentoring of trainees to generate and use research.

Evaluation of Enoxaparin Dosing as a Risk Factor for Bleeding in Lung Transplant Recipients.

BACKGROUND: Lung transplant recipients commonly develop complications that lead to anticoagulation. Standard FDA-approved enoxaparin dosing in this population results in a high incidence of above-goal anti-Xa levels, but its association with bleeding remains unclear. OBJECTIVE: To evaluate the association between enoxaparin dosing and bleeding in lung transplant recipients and assess the relationship between dosing and anti-Xa levels. METHODS: We conducted a single-center retrospective cohort study of adult lung transplant recipients who received therapeutic enoxaparin between 2000 and 2012 at a tertiary academic center. We dichotomized enoxaparin dosing regimens into standard dose (FDA-approved doses with a 10% rounding margin) and reduced dose. Clinicians ordered anti-Xa levels as deemed clinically appropriate. The primary outcome was major bleeding or clinically relevant nonmajor bleeding. RESULTS: Of 222 patients treated with enoxaparin, 33 (14.9%) had bleeding events, of which half (17/33) were major. Bleeding occurred in 25/146 (17.1%) patients who received standard-dose enoxaparin versus 8/76 (10.5%) patients who received reduced-dose enoxaparin (P = 0.190). Multiple logistic regression demonstrated an independent association between standard-dose enoxaparin and bleeding, after adjusting for confounders (adjusted odds ratio = 3.04; 95% CI = 1.14-8.10). The median enoxaparin dose in patients with above-goal versus at-goal anti-Xa levels was 0.89 versus 0.76 mg/kg every 12 hours; P = 0.006. However, doses yielding at-goal anti-Xa levels had an interquartile range of 0.67 to 0.90 mg/kg, which overlapped with doses yielding above- and below-goal anti-Xa levels. CONCLUSIONS: Enoxaparin dose reduction and anti-Xa level monitoring can improve drug safety and facilitate individualized dose optimization in lung transplant recipients.

Weight-based insulin dosing for acute hyperkalemia results in less hypoglycemia.

Hyperkalemia treatment with intravenous insulin has been associated with hypoglycemia. This single-center, retrospective study compared the effects on hypoglycemia between weight-based insulin dosing (0.1 U/kg of body weight up to a maximum of 10 U) compared to standard flat doses of 10 U among patients weighing less than 95 kg. Of the 132 charts randomly selected for review, hypoglycemic events (blood glucose <70 mg/dL) were reduced from 27.3% in the 10-U group to 12.1% in the weight-based group (P = 0.05). The number of affected patients was reduced with 19.7% in the 10-U group and 10.6% in the weight-based group (P = 0.22). The potassium-lowering effects of these 2 strategies were similar between groups. Female patients and those with baseline glucose values <140 mg/dL were at increased risk for hypoglycemia. Weight-based insulin dosing (0.1 U/kg) for acute hyperkalemia therapy resulted in less hypoglycemia without impacting potassium lowering. Journal of Hospital Medicine 2016;11:355-357. © 2016 Society of Hospital Medicine.

Impact of Vitamin K Administration on INR Changes and Bleeding Events Among Patients With Cirrhosis.

BACKGROUND: The efficacy of vitamin K in lowering an elevated INR in the setting of cirrhosis is not well established. OBJECTIVES: The purpose of this investigation is to determine the effect of vitamin K administration on the INR and bleeding eventsamong hospitalized patients with cirrhosis. METHODS: This is a retrospective investigation of patients hospitalized at an academic institution from 2010 to 2012. Adults with an ICD9 code supporting cirrhosis were segregated into matched cohorts based on provision of vitamin K. Multivariable logistic regression of factors associated with INR decrease and bleeding events was completed. RESULTS: The final matched cohort (n = 276) contained 130 patients who received vitamin K and 146 who did not receive this therapy. ICU care (adjusted odds ratio [AOR] = 2.91; 95% CI = 1.54-5.49; P = 0.01), receipt of a blood product (AOR = 2.40; 95%CI = 1.35-4.24; P = 0.03), and baseline INR > 1.6 (AOR = 1.72; 95% CI = 1.00-2.95; P = 0.05), but not vitamin K administration (AOR = 1.17; 95% CI = 0.66-2.08; P = 0.59), were associated with INR decrease. Bleeding events occurred more frequently among patients with a history of esophageal varices (AOR = 6.35; 95% CI = 1.21-33.4; P = 0.03), but vitamin K administration did not have an impact on these events (AOR = 4.90; 95% CI = 0.56-43.0; P = 0.15). CONCLUSIONS: Administration of vitamin K did not affect INR changes or bleeding events in this cohort of hospitalized patients with cirrhosis.

Analysis of enoxaparin dose titration at a large, tertiary teaching facility.

Therapeutic drug monitoring of enoxaparin with antifactor Xa levels (AXALs) is recommended in some populations; however, the approach to dose titration is poorly described. Our study at a large, tertiary teaching facility examined the dose response to titration of enoxaparin based on AXAL. Patients from 2008 to 2012 receiving enoxaparin were included, provided 2 or more steady state AXAL were obtained within 30 days and that the enoxaparin was prescribed for treatment rather than prophylaxis. The primary outcome was the percentage of dose change required to obtain goal range AXAL following dose titration. Eighty-seven patients were available for analysis with the following key characteristics: renal dysfunction during treatment 72%, obesity 8%, and solid organ transplant 26%. Initial goal AXAL was attained in 27 (31%) patients, and ultimately 54 (62%) patients achieved goal AXAL. Of the 31 patients who had initial AXAL above goal, 13 (42%) patients reached goal with a median dose decrease of 24%. In the 29 patients who had an initial AXAL below goal, 11 (38%) achieved therapeutic AXAL with a median dose increase of 16%. The AXAL monitoring can guide enoxaparin titration with subtherapeutic or supratherapeutic AXAL and an increase or decrease of roughly 20% is suggested as an initial change.

Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients.

Obesity increases the risk for venous thromboembolism (VTE), but whether high-dose thromboprophylaxis is safe and effective in morbidly obese inpatients is unknown. It was the objective of this study to quantify the efficacy and safety of high-dose thromboprophylaxis with heparin or enoxaparin in inpatients with weight > 100 kilograms (kg) within the BJC HealthCare system. Ina retrospective cohort study, we analysed 9,241 inpatients with weight > 100 kg discharged from three hospitals in the BJC HealthCare system from 2010 through 2012. We compared the incidence of VTE in patients who received high-dose thromboprophylaxis (heparin 7,500 units three times daily or enoxaparin 40 mg twice daily) to those who received standard doses (heparin 5,000 units two or three times daily or enoxaparin 40 mg once daily). The primary efficacy outcome was hospital-acquired VTE identified by International Classification of Diseases (ICD)-9 diagnosis codes. The primary safety outcome was bleeding events identified by ICD-9 codes. Among the 3,928 morbidly obese inpatients (weight > 100 kg and body mass index [BMI] ≥ 40 kg/m²), high-dose thromboprophylaxis approximately halved the odds of symptomatic VTE (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.27-1.00; p = 0.050). The rate of VTE was 1.48% (35/2,369) in these morbidly obese inpatients who received standard doses of thromboprophylaxis, compared to 0.77% (12/1,559) in those who received high doses. High-dose thromboprophylaxis did not increase bleeding (OR 0.84, 95% CI 0.66-1.07, p = 0.15). Independent predictors of VTE were surgery, male sex, cancer, and BMI. In conclusion, high-dose thromboprophylaxis nearly halves the rate of VTE in morbidly obese inpatients.

Assessment of bleeding events associated with short-duration therapeutic enoxaparin use in the morbidly obese.

BACKGROUND: Enoxaparin dosing for patients with morbid obesity is uncertain, and therefore, an elevated incidence of bleeding may exist in this group. OBJECTIVE: To determine if increased bleeding events occur in patients with morbid obesity (body mass index ≥ 40 kg/m(2)) compared with lower-weight patients with treatment doses of enoxaparin. METHODS: Patients at a single, academic medical center receiving enoxaparin for at least 24 hours from July to December 2009 were retrospectively evaluated. Patients with morbid obesity were randomly selected among the total cohort and were matched with lower-weight controls (1:2 ratio) based on the presence of renal dysfunction (serum creatinine >1.4 mg/dL). Bleeding events, defined on the basis of laboratory changes, administration of blood products, or clinical data, occurring up to 24 hours after enoxaparin administration were evaluated. Independent risk factors for bleeding were assessed via multivariate analysis. RESULTS: The maximum single dose administered throughout the study was 150 mg, and the largest patient enrolled weighed 175 kg. Final enoxaparin doses in morbidly obese (0.98 mg/kg) patients were lower compared with that in controls (1.04 mg/kg, P < .01). The proportion of patients with bleeding events was 29% in the morbidly obese and 23.5% in the control group (P = .30). Enoxaparin doses <0.9 mg/kg (adjusted odds ratio [AOR] = 2.35; 95% CI = 1.01-5.47; P = .04), durations of therapy beyond 48 hours (AOR = 2.42; 95% CI = 1.35-4.33; P < .01), and female gender (AOR = 2.05; 95% CI = 1.12-3.73; P = .02) were associated with bleeding, whereas warfarin use (AOR = 0.46; 95% CI = 0.26-0.81; P < .01) was associated with fewer bleeding events. CONCLUSIONS: Results suggest that dosing enoxaparin in morbidly obese patients (up to 175 kg in weight) with doses capped at 150 mg was not associated with increased bleeding incidence.

Role of new drugs for management of atrial fibrillation.

OBJECTIVE: To evaluate the role of newer agents in the management of atrial fibrillation (AF). DATA SOURCES: EMBASE and MEDLINE were searched (up to June 2012) combining medication names with atrial fibrillation, humans, clinical trials, and pharmacoeconomic. References of the articles identified and www.clinicaltrials.gov were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Studies were limited to the English language with clinical or pharmacoeconomic end points followed by the consensus of 3 authors. DATA SYNTHESIS: Formulated to reduce some of the adverse effects associated with amiodarone by removing the iodine component, dronedarone has improved clinical outcomes over placebo when used in paroxysmal or persistent AF; however, it is less efficacious than amiodarone. Worse outcomes with dronedarone have been seen in patients with heart failure or permanent AF. It has not been compared to antiarrhythmic agents other than amiodarone, and pharmacoeconomic evaluations are lacking. Dabigatran 150 mg is superior to warfarin in preventing stroke or systemic embolism and has been associated with lower rates of vascular-associated mortality. Although the rates of major bleeding were not significantly different between the 2 agents, gastrointestinal bleeding and myocardial infarction occurred more frequently with dabigatran. Dabigatran appears to have the most pharmacoeconomic benefit over warfarin in patients with a higher risk of stroke. Rivaroxaban is noninferior to warfarin for the prevention of stroke and systemic embolism, with no difference in the rates of major bleeding. Cost-effectiveness studies have not been performed with this agent at this time. In patients with AF who were not suitable candidates for warfarin, apixaban is superior to aspirin in preventing stroke or systemic embolism without increasing the risk for major bleeding. Additionally, apixaban is superior to warfarin in preventing stroke or systemic embolism, results in fewer bleeding events, and is associated with lower mortality. Apixaban is not cost-effective against aspirin when used for a short duration but gains superiority with prolonged use or in patients with higher risks of stroke. Additionally, apixaban appears to offer a pharmacoeconomic advantage over warfarin at no to minimal cost. Each new anticoagulant lacks a reversal agent and an assay to detect the presence of the anticoagulant, as well as long-term data when used in the clinical setting. CONCLUSIONS: Use of dronedarone should be limited to patients with paroxysmal or persistent AF and should not be used in patients with heart failure or with permanent AF. Newer antithrombotic agents appear to be promising alternatives for the prevention of stroke in patients with AF; however, more data are needed to understand their role.

Inpatient insulin orders: are patients getting what is prescribed?

BACKGROUND: In-hospital insulin administration is associated with many medication errors, but the frequency and reasons for insulin administration errors are poorly described. To document types and frequency of errors related to insulin administration, an examination of 4 units was conducted. METHODS: Using snapshot methodology, 4 non-intensive care unit (ICU) areas (medicine, cardiology, transplant, and surgery) were examined in an observational, prospective manner for 4 weeks. Each patient on insulin on the first day was followed for 7 days. Definitions and error categories were defined prior to data collection. Error types and numbers were collected and quantified on per-day or per-patient basis. RESULTS: A total of 116 patient audit periods covering a total of 378 inpatient hospital days were examined. Inpatient insulin regimens on day 1 included correctional insulin only (51.7% of cases), neutral protamine Hagedorn ([NPH] 12%), and glargine (28.4%). A total of 199 administration errors occurred at a rate of 1.72 errors/patient-period and 0.53 errors/patient day. Missing documentation of doses (15.5% of all patients) and insulin being held without an order (25% of patients) were the most frequently occurring events. Other errors include transcription (7.5%), timing errors (22.7%), and lack of documentation of physician notification of hypoglycemia (12.6%). CONCLUSIONS: Errors associated with insulin in the hospital are common and reveal a number of system errors that should be addressed. These data provide a foundation for future performance improvement.

Evaluation of therapeutic anticoagulation with enoxaparin and associated anti-Xa monitoring in patients with morbid obesity: a case series.

Our purpose was to describe anti-Xa levels, dosage requirements, and complications associated with enoxaparin treatment doses in patients with morbid obesity. Inpatients with a BMI >40 kg/m(2) at an academic medical center prescribed therapeutic enoxaparin from 2004 to 2010 who also had an associated anti-Xa level were included in this retrospective evaluation. Twenty-six patients were identified having median weight of 162 kg (range 106-243), median BMI of 49.5 kg/m(2) (range 40.1-98.1), and median enoxaparin duration of 4 days (range 1-32). Venous thromboembolism was the most common reason for anticoagulation (n = 19, 73%). The median starting dose was 0.8 mg/kg actual body weight (range 0.51-1; absolute dose 80-150 mg) every 12 h. Twelve patients (46%) achieved a goal anti-Xa level, 10 (38%) were above goal and 4 (15%) were uninterpretable. Among the 10 patients with anti-Xa levels above goal, the median initial dose was 0.85 mg/kg (range 0.75-1) versus 0.74 mg/kg (range 0.51-1) for patients at goal with similar median peak serum creatinine (PSCr) values between these two groups (P > 0.05). No bleeding events occurred in patients achieving goal anticoagulation versus 4/10 (40%) with high anti-Xa levels (P = 0.033) with similar median PSCr between these groups. No thrombotic events occurred while on therapy. The majority in this cohort with morbid obesity achieved anti-Xa levels at or above goal at doses less than the recommended 1 mg/kg every 12 h. Bleeding events were more frequent among patients with anti-Xa levels above goal, despite similar PSCr values.

Implementation of a real-time computerized sepsis alert in nonintensive care unit patients.

OBJECTIVE: Early therapy of sepsis involving fluid resuscitation and antibiotic administration has been shown to improve patient outcomes. A proactive tool to identify patients at risk for developing sepsis may decrease time to interventions and improve patient outcomes. The objective of this study was to evaluate whether the implementation of an automated sepsis screening and alert system facilitated early appropriate interventions. DESIGN: Prospective, observational, pilot study. SETTING: Six medicine wards in Barnes-Jewish Hospital, a 1250-bed academic medical center. PATIENTS: Patients identified by the sepsis screen while admitted to a medicine ward were included in the study. A total of 300 consecutive patients were identified comprising the nonintervention group (n=200) and the intervention group (n=100). INTERVENTIONS: A real-time sepsis alert was implemented for the intervention group, which notified the charge nurse on the patient's hospital ward by text page. MEASUREMENTS AND MAIN RESULTS: Within 12 hrs of the sepsis alert, interventions by the treating physicians were assessed, including new or escalated antibiotics, intravenous fluid administration, oxygen therapy, vasopressors, and diagnostic tests. After exclusion of patients without commitment to aggressive management, 181 patients in the nonintervention group and 89 patients in the intervention group were analyzed. Within 12 hrs of the sepsis alert, 70.8% of patients in the intervention group had received≥1 intervention vs. 55.8% in the nonintervention group (p=.018). Antibiotic escalation, intravenous fluid administration, oxygen therapy, and diagnostic tests were all increased in the intervention group. This was a single-center, institution- and patient-specific algorithm. CONCLUSIONS: The sepsis alert developed at Barnes-Jewish Hospital was shown to increase early therapeutic and diagnostic interventions among nonintensive care unit patients at risk for sepsis.

Comparison of bivalirudin and argatroban for the management of heparin-induced thrombocytopenia.

STUDY OBJECTIVES: To compare the effectiveness of bivalirudin and argatroban in achieving anticoagulation goals and to compare clinical outcomes assessing the safety and efficacy in patients with known or suspected heparin-induced thrombocytopenia (HIT). DESIGN: Single-center, retrospective analysis. SETTING: Large tertiary care academic medical center. PATIENTS: A total of 138 adults who received either bivalirudin (92 patients) or argatroban (46 patients) for at least 24 hours for known or suspected HIT between January 2007 and July 2008. MEASUREMENTS AND MAIN RESULTS. Data regarding demographics, direct thrombin inhibitor (DTI) dosing and monitoring, and related clinical outcomes were collected; statistical analysis was performed to compare results for patients receiving bivalirudin versus those receiving argatroban. Duration of DTI use ranged from 24-658 hours. At the time of DTI initiation, 108 patients (78%) were in an intensive care unit, with the highest proportion (61/138 [44%]) in the cardiothoracic surgery intensive care unit. The median (interquartile range [IQR]) DTI doses at the time of first reaching therapeutic goal were bivalirudin 0.06 mg/kg/hour (0.04-0.08 mg/kg/hr) and argatroban 1.0 µg/kg/minute (0.5-2.0 µg/kg/min). The median percentage of activated partial thromboplastin time (aPTT) values within therapeutic range while patients were receiving DTI therapy were similar for bivalirudin and argatroban (75% and 70%, respectively, p=0.238). A greater percentage of aPTT values were supratherapeutic with argatroban versus bivalirudin treatment (18% vs 8%, p=0.046). Median time to therapeutic goal was similar for bivalirudin (5.50 hrs [IQR 4-14.5 hrs]) and argatroban (5.75 hrs [IQR 3-17.7 hrs], p=0.499). New thromboembolic events occurred in seven patients (8%) receiving bivalirudin and two (4%) receiving argatroban (p=0.718). Bleeding events occurred at similar rates in both groups (9% for bivalirudin vs 11% for argatroban, p>0.999). CONCLUSIONS: Bivalirudin and argatroban were similar in achieving and maintaining therapeutic anticoagulation goals, clinical outcomes, and safety. This study suggests that bivalirudin represents an alternative in the management of HIT, but prospective studies are needed.

Identifying optimal initial infusion rates for unfractionated heparin in morbidly obese patients.

BACKGROUND: Most literature available for unfractionated heparin (UFH) supports the use of actual body weight for dosing all patients, yet a small proportion of the patients in these studies were morbidly obese. The most appropriate dosing strategy for therapeutic UFH in this patient population is not clearly defined. OBJECTIVE: To better define appropriate UFH dosing strategies in morbidly obese patients and to evaluate the safety of a weight-based heparin nomogram in this patient population. METHODS: Patients with class III (morbid) obesity receiving therapeutic doses of a UFH infusion for greater than 24 hours were evaluated. Two comparator groups of overweight/class I -II obesity and normal/underweight patients were created by matching patients to the class III obesity group. Doses and times to therapeutic activated partial thromboplastin time (aPTT), bleeding rates, and mortality were assessed. RESULTS: The mean infusion rate required to obtain a first therapeutic aPTT was 11.5 units/kg/h in the class III obesity group (n = 94) versus 12.5 units/kg/h and 13.5 units/kg/h for the overweight/class I-II obesity (n = 92) and normal/underweight (n = 87) groups, respectively (p = 0.001). The mean times to a first therapeutic aPTT were 21.3, 22.1, and 29.9 hours, respectively (p = 0.421). There was a statistically significant difference in the infusion rate required to obtain 2 consecutive therapeutic aPTTs between groups (p = 0.016), with higher weight groups requiring smaller (per kilogram actual body weight) infusion rates, but there was no significant difference in the time to reach 2 consecutive therapeutic aPTTs (p = 0.776). There was no significant difference in bleeding (p = 0.517) or mortality (p = 0.475) among groups. CONCLUSIONS: Morbidly obese patients require smaller UFH infusion rates per kilogram actual body weight compared to patients with lower body mass indices. UFH dosing recommendations should be modified to reflect body mass index classification.