Ampicillin-Sulbactam for Carbapenem-Susceptible Acinetobacter baumannii Pneumonia: A Case for High-Dose, Continuous Infusion Dosing Strategy in the Trauma ICU.

Background: The optimal ampicillin-sulbactam dosing regimen for carbapenem-susceptible Acinetobacter baumannii isolates in critically ill trauma patients has not been clearly defined. One strategy to provide the adequate sulbactam dose includes high-dose continuous infusion. Case(s) Description: We present three cases of critically ill trauma patients with augmented renal clearance treated with high-dose ampicillin-sulbactam through an intravenous continuous infusion for ventilator-associated pneumonia. All A. baumannii isolates were susceptible to sulbactam with low minimum inhibitory concentrations. All achieved clinical cure at the end of therapy and no recurrent pneumonia was noted. No clinically substantial adverse effect attributable to ampicillin-sulbactam therapy occurred. Discussion: There is limited evidence to endorse high-dose, continuous infusion ampicillin-sulbactam for treatment of infections caused by carbapenem-susceptible A. baumannii. This report presents three critically ill trauma patients with augmented renal clearance that achieved positive clinical outcomes with higher doses of ampicillin-sulbactam administered through a continuous infusion.

Association of piperacillin and vancomycin exposure on acute kidney injury during combination therapy.

Objectives: Acute kidney injury (AKI) is a well-documented adverse effect observed with piperacillin/tazobactam in combination with vancomycin. The pharmacokinetics of these antibiotics when given in combination have not been previously evaluated. The purpose of this study was to compare the exposure of vancomycin + piperacillin/tazobactam in patients with and without AKI. Methods: Ninety adult patients, who received at least 72 h of vancomycin + piperacillin/tazobactam combination therapy and had available serum concentrations of vancomycin and piperacillin were included in the study. Nephrotoxicity was defined as a 1.5-fold increase in serum creatinine within 7 days from baseline. Median daily AUCs were calculated in those with nephrotoxicity (vancomycin + piperacillin/tazobactam 'N') versus those without nephrotoxicity (vancomycin + piperacillin/tazobactam 'WN') during the first 7 days of combination therapy. Results: The overall incidence of AKI in those receiving vancomycin + piperacillin/tazobactam was 20% (18/90). The median daily vancomycin AUCs did not differ between the vancomycin + piperacillin/tazobactam 'WN' and vancomycin + piperacillin/tazobactam 'N' groups. Although not statistically significant, the median daily vancomycin AUCs in the vancomycin + piperacillin/tazobactam 'N' group were numerically greater on Day 5 and trended downwards thereafter. For the piperacillin group, the median daily AUCs did not vary between groups, except on Day 7 where the vancomycin + piperacillin/tazobactam 'WN' group had statistically greater median piperacillin AUC than the vancomycin + piperacillin/tazobactam 'N' group (P = 0.046). Conclusions: Utilizing serum creatinine-defined AKI, our study did not find any significant differences in vancomycin and piperacillin/tazobactam exposure between the groups with and without nephrotoxicity. These data indicate that vancomycin + piperacillin/tazobactam should not be avoided due to the risk of overexposure; instead, clinicians should continue to use these therapies cautiously.

Beta-lactam target attainment and associated outcomes in patients with bloodstream infections.

OBJECTIVES: To evaluate the association between early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters and therapy outcomes in bloodstream infection (BSI). METHODS: Adult patients who received cefepime, meropenem, or piperacillin/tazobactam for BSI and had concentrations measured were included. Beta-lactam exposure was generated and the time that free concentration remained above the minimum inhibitory concentration (fT>MIC) and four multiples of MIC (fT>4 × MIC) were calculated for times 0-24 h and 0-7 days of therapy. Multiple regression analysis was performed to evaluate the impact of PK/PD on microbiological and clinical outcomes. RESULTS: A total of 204 patients and 213 BSI episodes were included. The mean age was 58 years and weight 83 kg. Age, Sequential Organ Failure Assessment (SOFA) score, haemodialysis, Pitt bacteraemia score, and hours of empiric antibiotic therapy were significantly associated with certain outcomes and retained in the final model. In multiple regression analysis, fT>4 × MIC at 0-24 h and 0-7 days was a significant predictor of negative blood culture on day 7 (P=0.0161 and 0.0068, respectively). In the time-to-event analysis, patients who achieved 100% fT>4 × MIC at 0-24 h and 0-7 days had a shorter time to negative blood culture compared with those who did not (log-rank P=0.0004 and 0.0014, respectively). No significant associations were identified between PK/PD parameters and other outcomes, including improvement in symptoms at day 7 and 30-day mortality. CONCLUSION: Early and cumulative achievement of fT>4 × MIC was a significant predictor of microbiological outcome in patients with BSI.

Risk Factors for Delirium and Association of Antipsychotic Use with Delirium Progression in Critically Ill Trauma Patients.

BACKGROUND: Delirium occurs frequently in critically ill and injured patients and is associated with significant morbidity and mortality. Limited data exists on the risk factors for developing delirium in critically ill trauma patients and the effect of antipsychotic (AP) medications on delirium progression. OBJECTIVE: The objective of this study is to determine the incidence of delirium in critically ill trauma versus non-trauma surgical patients and determine if the presence of trauma was associated with intensive care unit (ICU) delirium. Secondary outcomes included identifying risk factors for delirium and determining the impact of AP medication use on delirium progression in critically ill trauma patients. METHODS: This retrospective review studies adult trauma/surgical ICU patients admitted between May 2017-July 2018 to a level I trauma and tertiary referral center. Regression modeling was used to determine the impact of AP use on delirium-free days. RESULTS: Delirium was more common in critically ill trauma patients versus non-trauma surgical ICU patients [54/157 (34.4%) vs 42/270 (15.6%), P < .001]. Of the 54 trauma patients with delirium, 28 (52%) received an AP medication for delirium treatment and in the multiple linear regression analysis, AP use was significantly associated with fewer delirium-free days (P = .02). DISCUSSION: Higher admission sequential organ failure assessment scores and increased length of stay were significantly associated with delirium onset in critically ill trauma patients. Use of AP medications for delirium treatment in this population had a negative impact on delirium-free days.

Impact of Piperacillin-Tazobactam Dosing in Septic Shock Patients Using Real-World Evidence: An Observational, Retrospective Cohort Study.

BACKGROUND: Sepsis and septic shock are associated with significant morbidity and mortality. Rapid initiation of appropriate antibiotic therapy is essential, as inadequate therapy early during septic shock has been shown to increase the risk of mortality. However, despite the importance of appropriate antibiotic initiation, in clinical practice, concerns for renal dysfunction frequently lead to antibiotic dose reduction, with scant evidence on the impact of this practice in septic shock patients. OBJECTIVE: The purpose if this article is to investigate the rate and impact of piperacillin-tazobactam dose adjustment in early phase septic shock patients using real-world electronic health record (EHR) data. METHODS: A multicenter, observational, retrospective cohort study was conducted of septic shock patients who received at least 48 hours of piperacillin-tazobactam therapy and concomitant receipt of norepinephrine. Subjects were stratified into 2 groups according to their cumulative 48-hour piperacillin-tazobactam dose: low piperacillin-tazobactam dosing (LOW; <27 g) group and normal piperacillin-tazobactam dosing (NORM; ≥27 g) group. To account for potential confounding variables, propensity score matching was used. The primary study outcome was 28-day norepinephrine-free days (NFD). RESULTS: In all, 1279 patients met study criteria. After propensity score matching (n = 608), the NORM group had more median NFD (23.9 days [interquartile range, IQR: 0-27] vs 13.6 days [IQR: 0-27], P = 0.021). The NORM group also had lower rates of in-hospital mortality/hospice disposition (25.9% [n = 79] vs 35.5% [n = 108]), P = 0.014). Other secondary outcomes were similar between the treatment groups. CONCLUSIONS AND RELEVANCE: In the propensity score-matched cohort, the NORM group had significantly more 28-day NFD. Piperacillin-tazobactam dose reduction in early phase septic shock is associated with worsened clinical outcomes. Clinicians should be vigilant to avoid piperacillin-tazobactam dose reduction in early phase septic shock.

Cefepime Daily Exposure and the Associated Impact on the Change in Sequential Organ Failure Assessment Scores and Vasopressors Requirement in Critically Ill Patients Using Repeated-Measures Mixed-Effect Modeling.

IMPORTANCE: Sepsis and septic shock are major healthcare problems that need early and appropriate management. OBJECTIVES: To evaluate the association of daily cefepime pharmacokinetic/pharmacodynamic (PK/PD) parameters with change in Sequential Organ Failure Assessment (SOFA) score and vasopressors requirement. DESIGN SETTING AND PARTICIPANTS: This is a retrospective study. Adult ICU patients who received cefepime for Gram-negative pneumonia or bloodstream infection (BSI) and had cefepime concentrations measured were included. Daily cefepime exposure was generated and PK/PD parameters calculated for patients. Repeated-measures mixed-effect modeling was used to evaluate the impact of PK/PD on the outcomes. MAIN OUTCOMES AND MEASURES: Change in daily SOFA score and vasopressors requirement. RESULTS: A total of 394 and 207 patients were included in the SOFA and vasopressors analyses, respectively. The mean (±sd) age was 55 years (19) and weight 81 kg (29). For the change in SOFA score, daily SOFA score, mechanical ventilation, renal replacement therapy, and number of vasopressors were included. In the vasopressors analysis, daily SOFA score, day of therapy, and hydrocortisone dose were significant covariates in the final model. Achieving cefepime concentrations above the minimum inhibitory concentration (MIC) (T>MIC) for 100% of the dosing interval was associated with 0.006 µg/kg/min decrease in norepinephrine-equivalent dose. Cefepime PK/PD did not have an impact on the daily change in SOFA score. CONCLUSIONS AND RELEVANCE: Achieving 100% T>MIC was associated with negligible decrease in vasopressors requirement in ICU patients with Gram-negative pneumonia and BSI. There was no impact on the change in SOFA score.

Using Machine Learning To Define the Impact of Beta-Lactam Early and Cumulative Target Attainment on Outcomes in Intensive Care Unit Patients with Hospital-Acquired and Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT>MIC) and the time free concentration remained above four multiples of the MIC (fT>4×MIC) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Pharmacy student self-assessment of strength of residency candidacy compared to clinical faculty.

INTRODUCTION: The purpose of this study was to compare student and faculty perceptions of strength of residency candidacy and to identify student preferences and perceptions that influence the process of being selected by a residency program beyond standard application materials. METHODS: A 31-item questionnaire was administered to third-year and fourth-year pharmacy students to collect information regarding factors deemed important for successful residency program candidacy. Global assessment of strength of residency candidacy was self-rated by students and a group of clinical faculty blinded to student responses. Interrater reliability for student-to-faculty and faculty-to-faculty perceptions of strength of residency candidacy was determined. RESULTS: Students generally reported good academic metrics and participation in a wide variety of scholarly activities deemed important in attaining a residency position. Students rated overall strength of residency candidacy as "above average" (n = 54, 37.2%), "average" (n = 60, 41.4%), and "below average" (n = 31, 21.3%), and self-perception increased with matriculation. Student self-assessment of strength of residency candidacy compared to faculty assessment showed poor agreement (mean [SD] kappa = 0.27 [0.08]). Faculty concordance in assessment of strength of residency candidacy was moderate (α = 0.55). CONCLUSIONS: Concordance in self-assessment of strength of residency candidacy of students compared to faculty was poor. In contrast, agreement among faculty was moderate with generally lower ratings compared to student self-rating, suggesting that students are overconfident in this regard. These findings support residency preparedness training in pharmacy curricula which should include formal assessment of strength of residency candidacy to identify gaps.

Impact of Empiric Linezolid for Necrotizing Soft Tissue Infections on Duration of Methicillin-Resistant Staphylococcus aureus-Active Therapy.

Background: Necrotizing soft tissue infections (NSTIs) require prompt surgical debridement and antimicrobial therapy. Indicated antimicrobial therapy involves broad-spectrum coverage against common pathogens and toxin inhibition. Linezolid provides both methicillin-resistant Staphylococcus aureus (MRSA) coverage and toxin inhibition, however, there is limited evidence evaluating its role in empiric treatment. The purpose of this study was to evaluate the impact of empiric linezolid use for NSTIs on the total duration of MRSA-active therapy. Patients and Methods: This retrospective, single-center study included adult surgical intensive care unit (ICU) patients treated with empiric vancomycin and clindamycin or linezolid along with gram-negative and anaerobe coverage for NSTIs. The primary end point of this study was the duration of MRSA-active therapy. Secondary end points included ICU and hospital length of stay (LOS; days), new-onset acute kidney injury (AKI), and Clostridioides difficile infection (CDI). Results: There were 21 patients in the vancomycin/clindamycin cohort and 28 patients in the linezolid cohort. The average duration of vancomycin was 3.9 days versus 2.9 days of linezolid (p = 0.04). The average hospital LOS for the vancomycin/clindamycin cohort was somewhat longer than the linezolid cohort, although the difference was not statistically significant (p = 0.07), and the incidence of new-onset AKI during hospitalization was higher in the vancomycin/clindamycin cohort (38.1% vs. 0%; p < 0.001). No differences were observed for ICU LOS or CDI. Conclusions: Empiric linezolid use for NSTI was associated with one less day of MRSA-active therapy and lower incidence of new-onset AKI during hospitalization. Linezolid was a safe and effective alternative to vancomycin/clindamycin for empiric treatment of NSTIs.

Nonocclusive mesenteric ischemia: A rare but lethal complication of enteral nutrition in critically ill patients.

BACKGROUND: The American Society for Parenteral and Enteral Nutrition (ASPEN)/ Society of Critical Care Medicine and the European Society for Clinical Nutrition and Metabolism guidelines recognize that critically ill patients receiving stable, low doses of vasopressors have experienced the advantages of early initiation of enteral nutrition (EN). However, clinical questions remained unanswered including vasopressor combinations associated with complications, the advent of other therapies during hypotensive states, as well as the volume and content of EN that might contribute to the development of a nonocclusive mesenteric ischemia (NOMI). PRESENTATION: A 68-year old male with a history of hypertension, hyperlipidemia, atrial fibrillation, coronary artery disease with two-vessel bypass grafting, and peripheral vascular disease underwent subtotal excision of an infected right axillofemoral-femoral bypass graft. Postoperatively, EN was held because of hemodynamic instability and postsurgical complications. A fiber-free, high-protein, and low-residue formula was started at 10 ml/h while the patient was receiving stable doses of midodrine, norepinephrine, and vasopressin. Despite advancement of tube-feed rates to goal, nasogastric output never exceeded 300 ml. Computerized tomography of the abdomen showed diffuse bowel distention with pneumatosis, concerning for bowel ischemia. No surgical interventions were pursued, and the patient died. CONCLUSIONS: Our patient developed NOMI postoperatively while receiving EN. Further studies addressing EN route, trophic vs full EN, recommended formula, the safety of vasoactive agents, the addition of fiber to EN, and continuous venovenous hemodiafiltration in relation to NOMI are needed, as there continues to be clinical controversy regarding these topics.

Cefepime Precision Dosing Tool: from Standard to Precise Dose Using Nonparametric Population Pharmacokinetics.

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate a cefepime population pharmacokinetic (PK) model and integrate it into a precision dosing tool for implementation. Two data sets (680 patients) were used to build the cefepime PK model in Pmetrics, and three data sets (34 patients) were used for the validation. A separate application data set (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 h-1 (adults) and 0.96 h-1 (children), the central volume of distribution was 13.85 L, and the rate of transfer from the central to the peripheral compartments was 1.22 h-1 and from the peripheral to the central compartments was 1.38 h-1. After integration in BestDose, the observed versus predicted cefepime concentration fit using the application data set was excellent (R2 > 0.98), and the median difference between what was observed and what BestDose predicted on a second occasion was 4%. For the OID, cefepime at a 0.5- to 1-g 4-h infusion every 8 to 24 h (q8 to 24 h) with a CrCl of <70 mL/min was needed to achieve a target range of free trough:MIC 1 to 4 at a MIC of 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation, and the median concentration prediction bias was 4%. The OID algorithm was provided.

Optimal Antibiotic Duration for Bloodstream Infections Secondary to Intraabdominal Infection.

BACKGROUND: Bloodstream infections (BSIs) secondary to intraabdominal infections (IAIs) are common in the intensive care unit (ICU). The Surgical Infection Society guidelines recommend treatment duration after achieving source control in patients with secondary bacteremia; however, literature supporting this recommendation is limited. The purpose of this study was to compare outcomes in patients who received shorter versus extended duration of antibiotics for bacteremia secondary to IAI. MATERIALS AND METHODS: A retrospective cohort analysis was conducted in adult surgical ICU patients (n = 42) with BSIs and source control procedure(s) for IAI. The primary outcome was recurrent IAI. Secondary outcomes included surgical site infections (SSIs), Clostridium difficile infections (CDIs), secondary fungal infections, and in-hospital mortality. RESULTS: Forty-two patients met inclusion criteria and were divided into groups according to antimicrobial duration; 12 patients received <7 d, and 30 patients received >7 d of antibiotics. There were no differences in baseline characteristics between the two cohorts except for the presence of sepsis [4/12 (33.3%) versus 27/30 (90.0%); P = 0.001]. Thirty-one percent (13/42) of all organisms isolated from blood cultures were gram-negative bacteria, 12/42 (28.6%) were MDROs, and 2/42 (4.8%) patients experienced a culture mismatch in which cultured bacteria were not susceptible to empiric antibiotic therapy. Rates of recurrent IAI were similar between the two cohorts [1/12 (8.3%) versus 4/30 (13.3%), P = 0.554]. CONCLUSIONS: Among surgical ICU patients with BSI secondary to IAI, cessation of antibiotic therapy within 7 d of source control was not associated with an increased incidence of recurrent IAI.

Intensive Care Unit Delirium in Surgical Patients Is Associated with Upregulation in Tryptophan Metabolism.

INTRODUCTION: In intensive care unit (ICU) patients, delirium is frequent, occurs early in ICU admission, and is associated with poor outcomes. Risk models based on clinical factors have shown variable performance in terms of predictive ability. Identification of a candidate biomarker that associates with delirium may lead to a better understanding of disease mechanism, validation biomarker studies, and the ability to develop targeted interventions for prevention and treatment of delirium. This study analyzed metabolite concentrations early in the course of ICU admission to assess the association with delirium onset. METHODS: Within 24 hours of ICU admission, blood samples for global and targeted metabolomics analyses in adult surgical ICU patients were collected prospectively. Metabolites were determined using mass spectrometry/ultra-high-pressure liquid chromatography and analyzed in patients with delirium and a group of controls matched on age, sex, and admission Sequential Organ Function Assessment (SOFA) score. RESULTS: Patients in the study (65 per group) were a mean age of 59 years, had a median SOFA score of 6, and were most commonly admitted to the ICU following major trauma. In the delirium group, median onset of delirium was 3 (interquartile range 1-6) days, and the most common delirium subtype was mixed (56%). Kynurenic acid was significantly increased, and tryptophan concentration was significantly decreased in the delirium group (p=0.04). The ratio of kynurenine-to-tryptophan concentration was significantly higher in the delirium group (p=0.005). CONCLUSIONS: Evidence of upregulation was found in the tryptophan metabolic pathway in delirious patients because tryptophan concentrations were lower, tryptophan metabolites were higher, and the kynurenine-to-tryptophan ratio was increased. These findings suggest a role of increased inflammation and accumulation of neurotoxic metabolites in the pathogenesis of ICU delirium. Future studies should target this pathway to validate metabolites in the tryptophan pathway as risk biomarkers in patients with ICU delirium.

An Update on Existing and Emerging Data for Meropenem-Vaborbactam.

PURPOSE: The search for new agents to treat multidrug-resistant gram-negative bacterial infections has been ongoing. Specifically, carbapenem-resistant Enterobacteriaceae (CRE) infections often exhibit multiple resistance mechanisms, including alterations in drug structure, bacterial efflux pumps, and drug permeability. Vaborbactam, a cyclic boronic acid pharmacophore, has the highest potency in vitro with meropenem as an inhibitor of class A carbapenemases, including Klebsiella pneumoniae carbapenemase (KPC). This combination product was approved by the US Food and Drug Administration for complicated urinary tract infections (cUTIs) in August 2017, and recent Phase III trial data have expanded the literature available. This article aimed to describe the literature regarding spectrum of activity, dosing and administration, including pharmacokinetic and pharmacodynamics properties, safety profile, and efficacy end points. METHODS: The terms meropenem, vaborbactam, RPX7009, and meropenem-vaborbactam were used to search for literature via PubMed, ClinicalTrials.gov, and published abstracts from 2013 to July 2019. Abstracts from IDWeek 2019 were also searched via these terms. Results were limited to availability in English. FINDINGS: Meropenem-vaborbactam covers a spectrum of gram-negative bacterial pathogens, including K pneumoniae, Escherichia coli, and Enterobacter cloacae complex. Although the addition of vaborbactam to meropenem results in MIC lowering for KPC-positive Enterobacteriaceae, in vitro data reveal limited activity against resistant strains of Acinetobacter species and Pseudomonas aeruginosa. Data from 2 Phase III studies compare the drug with available therapies for the following indications: cUTIs, acute pyelonephritis, hospital-acquired and ventilator-acquired bacterial pneumonia, bacteremia, and complicated intra-abdominal infections. Outcomes include an improvement in clinical success when compared with piperacillin-tazobactam (98.4% vs 94%; 95% CI, 0.7%-9.1%; P < 0.001 for noninferiority) for overall treatment of cUTIs and acute pyelonephritis and clinical cure (64.3% vs 33.3%; P = 0.04) when compared with best available therapy for CRE infections in various sites of infection. Adverse events have been described as mild to moderate, with few events requiring discontinuation of the drug therapy. IMPLICATIONS: Currently, meropenem-vaborbactam is approved for treatment of cUTIs and acute pyelonephritis; however, off-label use, in particular for CRE infections, appears beneficial. Clinical trials to date have found an improvement in clinical cure and potentially an improved tolerability compared with standard therapies. Most of the evidence for meropenem-vaborbactam activity and the role in therapy focuses on KPC-producing organisms; however, because in vitro activity has been found with some non-KPC-producing CRE, its role may be further described from upcoming in vivo cases and postmarketing research.

Recent Updates in the Pharmacological Management of Sepsis and Septic Shock: A Systematic Review Focused on Fluid Resuscitation, Vasopressors, and Corticosteroids.

OBJECTIVE: Describe recent developments in the pharmacological management of sepsis and septic shock, focusing on fluid resuscitation, vasopressors, and corticosteroids. DATA SOURCES: A literature search limited to randomized controlled trials written in the English language reporting mortality and other clinically relevant outcomes that were published from July 1, 2016, to August 31, 2018, in patients aged ≥ 18 years. Titles and abstracts were reviewed for relevance. References for pertinent review articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant randomized controlled trials conducted in patients meeting the pre-defined inclusion criteria were considered for inclusion. DATA SYNTHESIS: From an initial search that identified 147 studies, 14 original research studies met inclusion criteria and were included in this review. Risk of bias (ROB) was assessed using the Revised Cochrane ROB assessment tool, with most included studies having a low ROB. Relevance to Patient Care and Clinical Practice: Sepsis and septic shock pose a significant burden on public health. Despite advances in our understanding of sepsis, mortality remains unacceptably high. Recent developments in the pharmacological management of septic shock have focused on determining optimal composition and dosage of fluid resuscitation, enhanced use of vasopressor therapy, and clarifying the role of corticosteroids. This systematic review will provide recommendations for application to practice focusing on recent research on these topics. CONCLUSIONS: Although recent developments in the pharmacological management of sepsis are encouraging, clinicians must be keen to utilize patient-specific factors to guide therapy and continue to strive to address the remaining unanswered questions.

A Systematic Review of ICU and Non-ICU Clinical Pharmacy Services Using Telepharmacy.

OBJECTIVE: To assess the impact of telepharmacy services in the acute care setting. DATA SOURCES: EMBase, MEDLINE, and SCOPUS database searches were performed through April 2018. STUDY SELECTION AND DATA EXTRACTION: PRISMA guidelines were applied for this systematic review. All English-language studies meeting the criteria of the following population, intervention, comparison, and outcome question were included: What impact does the provision of inpatient clinical pharmacy services delivered via telemedicine have on patient outcomes compared with standard of care? DATA SYNTHESIS: A total of 11 studies were identified for the acute care setting, including 3 for critically ill patients. All studies demonstrated a positive impact on patient outcomes, nursing satisfaction, and disease management. Varying modes of telepharmacy technology were used, such as remote access to electronic medical records, faxing or scanning documents, pictures or webcams. For communication purposes, telepharmacists used email or electronic communication, facsimile, video review, or telephone to speak directly with hospital personnel and patients. Relevance to Patient Care and Clinical Practice: Inpatient telepharmacy is feasible and should be leveraged to further enhance patient care by complementing existing service models. CONCLUSIONS: Telepharmacy services enhanced patient outcomes, improved nursing satisfaction, and expanded services within inpatient settings. Similar technologies were leveraged in non-intensive care units (ICUs) and ICUs, but the goals of telepharmacy appeared to differ. ICUs focused on an expansion of services in the ICU and non-ICUs addressed improved patient outreach in rural areas.

Characterization of Guideline Evidence for Off-label Medication Use in the Intensive Care Unit.

BACKGROUND: Non-Food and Drug Administration (FDA) or off-label medication prescribing occurs commonly in the intensive care unit (ICU). Off-label medication use creates a concern for untoward adverse effects; however, this worry may be alleviated by supportive literature. OBJECTIVE: To evaluate the evidence behind off-label medication use by determining the presence of guideline support and compare graded recommendations to an online tertiary resource, DRUGDEX. METHODS: Off-label medication use was identified prospectively over 3 months in medical ICUs in 3 academic medical centers. Literature searches were conducted in PubMed and the national guideline clearinghouse website to determine the presence of guideline support. DRUGDEX was also searched for strength-of-evidence ratings to serve as a comparator. RESULTS: A total of 287 off-label medication indication searches resulted in 44% (126/287) without identified evidence; 253 guidelines were identified for 56% (161/287) of indications. Of the published guidelines, 89% (226/253) supported the off-label indication. In the DRUGDEX comparison, 67% (97/144) of guideline gradings disagree with DRUGDEX, whereas 33% (47/144) of the gradings matched the online database. CONCLUSION: Because more than half of off-label medication use has the benefit of supportive guidelines recommendations and a majority of gradings are inconsistent with DRUGDEX, clinicians should consider utilizing guidelines to inform off-label medication use in the ICU. Still, there is a considerable amount of off-label medication use in the ICU that lacks supporting evidence, and use remains concerning because it may lead to inappropriate treatment and adverse events.

Impact of Intraoperative Continuous-Infusion Versus Intermittent Dosing of Cefazolin Therapy on the Incidence of Surgical Site Infections After Coronary Artery Bypass Grafting.

STUDY OBJECTIVES: To determine whether intraoperative continuous-infusion (CI) cefazolin reduces the incidence of surgical site infections (SSIs) compared with intermittent (INT) cefazolin dosing in patients undergoing coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB); safety end points and protocol adherence comparing the two dosing strategies were also explored. DESIGN: Retrospective quasi-experimental (pre-post intervention) cohort study. SETTING: Large academic medical center. PATIENTS: A total of 516 adults who underwent CABG on CPB and received cefazolin intraoperatively between June 1, 2013, and December 31, 2014, were included. The INT cohort included 284 patients who underwent CABG from June 2013 to February 2014. The CI cohort included 232 patients who underwent CABG from April to December 2014, after an intraoperative CI cefazolin protocol for cardiac surgery patients undergoing CPB was adopted in March 2014. MEASUREMENTS AND MAIN RESULTS: The primary end point was incidence of SSIs, and safety end points of renal dysfunction and seizures were evaluated. Multivariable logistic regression analysis was used to determine the impact on SSIs when controlling for other risk factors. A subgroup analysis for this study included 2 months within each time period to evaluate protocol adherence. The overall incidence of SSIs was decreased in patients receiving CI cefazolin, although this did not reach statistical significance (4.6% in the INT cohort vs 1.7% in the CI cohort, p=0.116). Superficial SSIs were significantly reduced in the CI cohort (2.8% in the INT cohort vs 0.4% in the CI cohort, p=0.039). In the regression analysis, CI cefazolin decreased the odds of SSI by 66%, although it did not reach statistical significance (p=0.077). Safety end points were not significantly different between groups. Overall protocol adherence did not differ significantly between the cohorts: 77% in the INT cohort and 67% in the CI cohort (p=0.212). CONCLUSION: CI cefazolin significantly decreased the incidence of superficial SSIs compared with INT cefazolin in patients undergoing CABG on CPB, without increasing the risk for adverse effects. As this study was underpowered to detect a significant difference in overall SSIs, larger, randomized studies are required to validate the superiority of CI cefazolin.

Continuous Intraoperative Cefazolin Infusion May Reduce Surgical Site Infections During Cardiac Surgical Procedures: A Propensity-Matched Analysis.

OBJECTIVES: The authors sought to determine whether an institutional transition from intermittent to continuous dosing of intraoperative antibiotics in cardiac surgery affected surgical site infection (SSI) outcomes. DESIGN: A retrospective chart review utilizing propensity matching. SETTING: A single academic, tertiary care hospital. PARTICIPANTS: One thousand one hundred seventy-nine patients undergoing coronary artery bypass grafting (CABG) and/or cardiac valvular surgery between April 2013 and November 2014 who received perioperative cefazolin. INTERVENTIONS: By method of cefazolin administration, patients were divided into an "intermittent-dosing" (ID) group and a "continuous-infusion" (CI) group. MEASUREMENTS AND MAIN RESULTS: Of the 1,179 patients who underwent cardiac surgery during the study period, 1:1 propensity score matching yielded 399 patients in each group. Rates of diabetes (33.6% ID v 33.8% CI, p = 0.94), coronary artery bypass (62.3% v 61.4%, p = 0.66), and bilateral internal mammary artery harvesting (6.0% v 8.3%, p = 0.22) were similar between groups. SSIs occurred in more ID patients than CI patients (2.3% v 0.5%, p = 0.03). This difference was driven by decreases in extremity and conduit harvest site SSIs (1.8% v 0.3%, p = 0.03), as there were no episodes of mediastinitis, and superficial sternal SSI rates did not differ (0.5% v 0.3%, p = 0.56). There also were significantly fewer episodes of pneumonia in the CI group (6.0% v 2.3%, p = 0.008). Intensive care unit and total lengths of stay did not differ. Thirty-day mortality was 2.8% in both groups (p = 1.00). CONCLUSIONS: As compared to ID regimens, CI cefazolin infusion may reduce post-cardiac surgery infectious complications. Further study in larger patient populations is needed.