Azithromycin and Septic Shock Outcomes.

Introduction: Although there is evidence describing the immunomodulatory effects of macrolide antibiotics, there is little literature exploring the clinical effects these properties may have and their impact on measurable outcomes. Objective: The purpose of this study was to determine if empiric antimicrobial regimens containing azithromycin shorten time to shock resolution. Methods: A retrospective study was performed in adults with septic shock admitted to intensive care units (ICUs) of 3 university-affiliated, urban teaching hospitals between June 2012 and June 2016. Eligible patients with septic shock required treatment with norepinephrine as the first-line vasopressor for a minimum of 4 hours and received at least 48 hours of antimicrobial treatment from the time of shock onset. Propensity scores were utilized to match patients who received azithromycin to those who did not. Results: A total of 3116 patients met initial inclusion criteria. After propensity score matching, 258 patients were included, with 124 and 134 patients in the azithromycin and control groups, respectively. Median shock duration was similar in patients treated with or without azithromycin (45.6 hr vs 59.7 hr, P = .44). In-hospital mortality was also similar (37.9% vs 38.1%, P = .979). There were no significant differences in mechanical ventilation duration, ICU length of stay (LOS), or hospital LOS. Conclusions: In patients admitted to the ICU with septic shock, empiric azithromycin did not have a significant effect on shock duration, mechanical ventilation duration, ICU LOS, hospital LOS, or in-hospital mortality.

Conducting Multicenter Residency Research.

PURPOSE: Conducting well designed pharmacy resident research projects has inherent challenges including inadequate sample size, a lack of time, decreased generalizability, and inadequate research support. A way to overcome these barriers is through conducting multicenter research projects. However, this approach may also bring new challenges. Therefore, the purpose of this article is to provide a general approach for pharmacy preceptors and leaders on implementation of multicenter residency research. SUMMARY: This article includes a general approach to conducting multicenter research from experienced individuals based upon their successes and failures. A timeline-based format is presented to lay the groundwork for implementation of this approach. Key topics in this paper include establishing a research overview committee, research question development, Institutional Review Board considerations, site recruitment, authorship discussions, resident coordination, protocol development, data collection, manuscript development, and considerations after residency. The approach maintains a critical focus on the individual residents ability to achieve American Society of Health-System Pharmacists accreditation standards for conducting research while operating in a collaborative manner. CONCLUSION: Conducting multicenter residency research projects requires a team-based approach and advanced planning. This approach has the potential to improve pharmacy resident project quality.

Outcomes associated with apixaban vs warfarin in patients with renal dysfunction.

Apixaban in patients with impaired renal function is supported by limited data. Landmark clinical trials evaluating apixaban in patients with atrial fibrillation and/or acute venous thromboembolism excluded patients with creatinine clearance (CrCl) <25 mL/min. This multicenter, retrospective chart review was conducted to evaluate the safety and effectiveness of apixaban compared with warfarin in patients with CrCl <25 mL/min. Included patients were newly initiated on apixaban or warfarin for at least 45 days with a CrCl <25 mL/min. Patients were evaluated for thrombosis and bleeding outcomes 6 months following initiation of anticoagulation. The primary outcome was the time to first bleeding or thrombosis event. A total of 128 patients met inclusion criteria in the apixaban group and 733 patients in the warfarin group. Time to first bleeding or thrombosis event was significantly different between the apixaban and warfarin groups. Cox proportional hazards model was conducted to control for potential confounding factors for the primary outcome. After controlling for atrial fibrillation and coronary artery bypass grafting, risk of thrombotic and bleeding events was lower in the apixaban group (hazard ratio, 0.47; 95% confidence interval, 0.25-0.92). There was not a statistical difference between time to thrombosis (83 days vs 54 days, P = .648), rate of thrombosis (5.5% vs 10.3%, P = .08), time to bleeding (46 days vs 54 days, P = .886), or rate of bleeding (5.5% vs 10.9%, P = .06). The severity of bleeding and thrombotic events was not different between groups. Apixaban may serve as a reasonable alternative compared with warfarin in patients with severe renal dysfunction.

Evaluation of a multidisciplinary approach to reduce internal medicine readmissions using a readmission prediction index.

PURPOSE: Readmission prediction indices are used to stratify patients by the risk of hospital readmission. We describe the integration of a 30-day hospital readmission prediction index into the electronic medical record (EMR) and its impact on pharmacist interventions during transitions of care (TOC). METHODS: A retrospective cohort study was conducted to compare 30-day readmission rates between adult internal medicine inpatients admitted by a multidisciplinary team providing TOC services (the TOC group) and those who received usual care (the control group). Interventions by a pharmacist serving on the TOC team were guided by an EMR-integrated readmission index, with patients at the highest risk for readmission receiving targeted pharmacist interventions. Inpatient encounters (n = 374) during the 5-month study period were retrospectively identified. Chi-square and Mann-Whitney U tests were performed to analyze differences in nominal and nonparametric continuous variables, respectively. Logistic regression was performed to identify variables associated with 30-day readmissions. The log-rank test was used to analyze hazard ratios for readmission outcomes in the 2 cohorts. RESULTS: Thirty-day readmission rates did not differ significantly in the TOC group and the control group (20.9% vs 18.3%, P = 0.52). However, patients who received additional direct pharmacist interventions, as guided by use of a hospital readmission index, had a lower 30-day readmission rate than patients who did not (11.4% vs 21.7%, P = 0.04). The readmission index score was significantly associated with the likelihood of 30-day readmission (odds ratio for readmission, 1.25; 95% confidence interval, 1.16-1.34; P < 0.01). The difference in unadjusted log-rank scores at 30 days with and without pharmacist intervention was not significant (P = 0.05). A mean of 4.5 medication changes were identified per medication reconciliation performed by the TOC pharmacist. CONCLUSION: A multidisciplinary TOC team approach did not reduce the 30-day readmission rate on an internal medicine service. However, patients who received additional direct pharmacist interventions guided by a readmission prediction index had a reduced readmission rate.

Development of an iterative validation process for a 30-day hospital readmission prediction index.

PURPOSE: A study was conducted to determine if an iterative validation process could maintain or improve the discriminative and predictive capabilities of a 30-day hospital readmission prediction index over 2.5 years. METHODS: Patient admissions were retrospectively identified using the electronic medical record. The receiver operating characteristic curve was used to assess model discrimination. Prediction index specificity, sensitivity, and positive and negative predictive values were also assessed. A rolling iterative validation process was developed in which patient admissions were divided into 3-month cohorts. Each cohort was analyzed individually and then included into the cumulative patient cohort and analyzed again. RESULTS: From 121,277 patient visits, an iterative validation approach maintained the discrimination (0.71 to 0.72), predictive validity, and overall accuracy (80.9% to 81.7%) of the 30-day readmission prediction index over 2.5 years. Index sensitivity and negative predictive value increased from baseline while specificity and positive predictive value remained largely unchanged. None of the assessed index parameters diminished or became less useful over the course of the study. CONCLUSION: An internal iterative validation process based on frequentist statistics maintained the discriminative ability and accuracy of a readmission index over 2.5 years despite numerous changes in the variables associated with readmission in the patient population.

Derivation and validation of a hospital all-cause 30-day readmission index.

PURPOSE: The study derives and validates a 30-day hospital readmission risk index to predict a patient's likelihood of readmission, utilizing a health systems electronic medical record. METHODS: A retrospective data extraction and analysis was conducted using data from the electronic medical record to identify risks of 30-day all-cause hospital readmission on adult patients admitted to a large multi-site health system. Univariate and multivariable logistic regression was performed on a derivation cohort of hospital admissions (n = 40,668) and analyzed 91 variables associated with 30-day hospital readmission. A 10-variable risk prediction equation was generated and validated in a second patient cohort (n = 7,820). The prediction index's discriminative ability was determined using the c-statistic, and calibration of the prediction index was assessed with the use of the Hosmer-Lemeshow test. RESULTS: The hospital all-cause thirty-day readmission index (HATRIX) identified 10 variables to be highly associated with 30-day readmission. The discriminative ability of the derived prediction equation was determined using the c-statistic and was calculated to be 0.73 (95% confidence interval [CI] 0.72-0.73) for the derivation cohort. The prediction equation was validated using a second cohort of patients and resulted with an area under the curve (AUC) of 0.72 (95% CI 0.70-0.73), indicating modest discrimination. CONCLUSION: An original risk prediction index for 30-day hospital readmission was derived and validated using 2 cohorts of patients. Identifying patients who have an increased risk of 30-day hospital readmission with the use of the electronic medical record is an ideal method for targeting interventions and improving transitions-of-care to reduce hospital readmissions.

Increased Enoxaparin Dosing Requirements for Treatment of Deep Vein Thrombosis in a Severely Burned Patient: Case Report and Literature Review.

Dosing of enoxaparin for deep vein thrombosis (DVT) prophylaxis in acutely burned patients has been shown to result in anti-Xa levels below target range. We describe the first case report, to our knowledge, of a severely burned patient who, despite prophylactic dosing of enoxaparin 30 mg subcutaneously twice daily, developed an acute DVT that required high-dose enoxaparin (100 mg [1.5 mg/kg] subcutaneously every 8 hours) to maintain anti-Xa levels within the therapeutic range (0.6-1 IU/ml). Pharmacokinetic evaluations were performed using anti-Xa levels measured throughout the patient's hospital stay to validate the appropriateness of this high-dose regimen based on established therapeutic anti-Xa level ranges. These results suggest that routine anti-Xa level monitoring, regardless of enoxaparin dosing, is necessary for burn patients who are receiving enoxaparin given their hypermetabolic state following injury.

A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity.

Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.

The Retrospective Cohort of Extended-Infusion Piperacillin-Tazobactam (RECEIPT) study: a multicenter study.

STUDY OBJECTIVE: To compare the effectiveness of extended-infusion piperacillin-tazobactam with that of similar-spectrum, nonextended-infusion [H9252]-lactam antibiotics in the treatment of gram-negative infections. DESIGN: Multicenter, retrospective medical record review. SETTING: Fourteen hospitals throughout the United States. PATIENTS: A total of 359 adults treated for gram-negative infections between January 1, 2007, and February 28, 2010, with either 4-hour extended-infusion piperacillin-tazobactam (186 patients) or nonextended-infusion comparator antibiotics (173 patients), which consisted of cefepime, ceftazidime, imipenem-cilastatin, meropenem, doripenem, or piperacillin-tazobactam. MEASUREMENTS AND MAIN RESULTS: Deidentified data were collected on demographics, renal function, Acute Physiology and Chronic Health Evaluation II score, chronic health conditions, source of infection and type of organism, intensive care unit (ICU) length of stay, total length of stay, type and duration of antimicrobial therapy, and in-hospital mortality. The primary outcome was mortality rate of the patients receiving extended-infusion piperacillin-tazobactam versus those receiving nonextended-infusion comparator antibiotics. Secondary outcomes were hospital length of stay, ICU length of stay, and total duration of antibiotic therapy. Baseline characteristics were similar between groups, except a significantly lower proportion of patients in the extended-infusion group were treated with a concomitant intravenous aminoglycoside (5.9% vs 16.2%, p<0.01), were infected with Pseudomonas species (22.6% vs 39.9%, p<0.01), or had positive respiratory cultures (30.7% vs 43.4%, p=0.01). Antibiotic duration, hospital length of stay, and ICU length of stay were similar between groups. In-hospital mortality was significantly decreased in the extended-infusion piperacillin-tazobactam group versus those receiving comparator antibiotics (9.7% vs 17.9%, p=0.02). Multivariate analysis confirmed that extended-infusion piperacillin-tazobactam prolonged survival by 2.77 days (p<0.01) and reduced the risk of mortality (odds ratio 0.43, p=0.05). CONCLUSION: Pharmacodynamic dosing using extended-infusion piperacillintazobactam demonstrated favorable outcomes, including mortality, when compared with nonextended-infusion, similar-spectrum [H9252]-lactams in the treatment of patients with documented gram-negative infections. Prospective, randomized trials are needed to further corroborate these findings.

Infectious diseases in the critically ill patients.

Infection is common in the critically ill and often results due to the severity of the patient's illness. Recent data suggest 51% of intensive care unit (ICU) patients are infected, and 71% receive antimicrobial therapy. Bacterial infection is the primary concern, although some fungal infections are opportunistic. Infection more than doubles the ICU mortality rate, and the costs associated with infection may be as high as 40% of total ICU expenditures. There are many contemporary antimicrobial resistance concerns that the critical care clinician must consider in managing the pharmacotherapy of infection. Methicillin resistance in Staphylococcus aureus, vancomycin resistance in Enterococci, beta-lactamase resistance in Enterobacteriaceae, multidrug resistance in Pseudomonas aeruginosa and Acinetobacter species, fluoroquinolone resistance in Escherichia coli, and fungal resistance are among the most common issues ICU clinician's must face in managing infection. Critical illness causes changes in pharmacokinetics that influence drug and dosing considerations. Absorption, distribution, metabolism, and excretion may all be affected by the various disease states that define critical illness. Several specific diseases are discussed, including ventilator-associated pneumonia, various fungal infections, gastrointestinal infections due to Clostridium difficile, urinary tract infections, and bloodstream infections. Within each disease section, discussion includes causes and prevention strategies, microbiology, evidence-based guidelines, and important caveats.

Maraviroc: a coreceptor CCR5 antagonist for management of HIV infection.

PURPOSE: The mechanism of action, pharmacology, pharmacokinetics, clinical efficacy, drug interactions, adverse effects, dosage and administration, cost, and role in therapy of maraviroc are reviewed. SUMMARY: Maraviroc is the first CCR5 coreceptor antagonist to receive marketing approval from the Food and Drug Administration (FDA) for the treatment of CCR5-tropic human immunodeficiency virus (HIV) infection as part of an optimized antiretroviral regimen in treatment-experienced patients. As 50% or more of treatment-experienced patients may be infected with CXCR4-tropic virus, a tropism assay should be performed before initiating maraviroc therapy. The majority of evidence supporting maraviroc's use comes from two studies of HIV-infected, treatment-experienced patients. Pooled analysis from these two studies revealed that twice-daily maraviroc decreased HIV-1 RNA by 1.84 log copies/mL, compared with 0.78 log copy/mL with placebo. Forty-six percent of subjects attained an HIV-1 RNA concentration of <50 copies/mL, compared with only 17% with placebo. In a trial of treatment-naive HIV-infected individuals, maraviroc failed to show noninferiority to efavirenz. Maraviroc is metabolized by cytochrome P-450 isoenzyme 3A4 and is subject to interactions with inhibitors and inducers of that isoenzyme, such as the protease inhibitors (except tipranavir), efavirenz, and rifampin. Resistance has been reported with maraviroc, but specific mechanisms are still poorly understood. The most common adverse effects reported with maraviroc were diarrhea, nausea, fatigue, and headache. CONCLUSION: Available data support the use of maraviroc, the first CCR5 antagonist to receive FDA marketing approval, as part of an optimized antiretroviral regimen in treatment-experienced patients infected with CCR5-tropic HIV.