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As was experienced across the country, the COVID-19 pandemic reached Colorado in early spring 2020. Yet, unlike many of the early hotspots in other states, the initial cases in Colorado surfaced in rural areas. It was evident early on it would be a public health crisis unlike anything Colorado had ever faced. There was an urgent need for rapid dissemination of up-to-date information and practice support provided by a multidisciplinary task force of academic health center and state public health experts working collaboratively to meet these needs. This article provides a roadmap for the development of a similar model, a community-connected Extension for Community Health Outcomes (ECHO) program based at an academic medical center and its ability to facilitate the service rapidly and scale to need.

Tedizolid has activity against Gram-positive pathogens as well as Mycobacterium spp and Nocardia spp. Real-world evidence supporting long-term tolerability and clinical success of tedizolid is lacking. Prolonged tedizolid therapy (median, 188 days; interquartile range, 62–493 days) appeared to be well tolerated in 37 patients (8.1% experienced adverse effect leading to discontinuation). Clinical success was 81.3% in those evaluated.

Clostridioides difficile infection (CDI) is a common complication in the hematopoietic stem cell transplantation (HSCT) and hematologic malignancy (HM) population. CDI is associated with increased hospital length of stay, health care and societal costs, morbidity, and mortality. Identifying strategies for secondary prevention of CDI is of extreme importance in the HSCT/HM population. In this study, our primary objective was to evaluate the effectiveness and safety of an oral vancomycin prophylaxis (OVP) protocol for secondary prevention of CDI in a retrospective cohort of adult autologous/allogeneic HSCT recipients and patients with HM who did not undergo HSCT with a first CDI episode treated with concomitant broad-spectrum antibiotics (BSA). Patients were diagnosed and treated for CDI as inpatients and/or outpatients and were divided into 2 groups based on a preprotocol versus postprotocol analysis: the OVP group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently received OVP posttreatment and a no OVP (NOVP) group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently did not receive OVP posttreatment. OVP was defined as vancomycin 125 mg every 12 hours for up to 7 days after BSA discontinuation. The primary endpoint was recurrent CDI (rCDI), defined as symptoms of loose stools/diarrhea with high clinical suspicion for CDI prompting empiric therapy within 60 days of completion of treatment/prophylaxis for the first CDI episode. The incidence of vancomycin-resistant enterococcal (VRE) infection and 60-day mortality were also compared between the 2 groups. Multivariate logistic regression was created from associated variables to identify independent associations with rCDI. A total of 50 patients were included, 21 in the OVP group (42%) and 29 in the NOVP group (58%). The mean patient age was 58 years, and the cohort was 60% male and 86% Caucasian. HSCT was performed in 60% of the patients, and 76% of CDI cases were diagnosed during hospitalization. The rate of rCDI was significantly lower in the OVP group compared with the NOVP group (5% [1 of 21] versus 35% [10 of 29]; P= .016), with no subsequent increase in VRE infection rate (14% [3 of 21] versus 10% [3 of 29]; P = .686). By multivariable logistic regression, rCDI was inversely associated with OVP (odds ratio [OR], .14; 95% confidence interval [CI], .007 to .994; P = .049) and directly associated with outpatient CDI diagnosis (OR, 8.72; 95% CI, 1.816 to 49.158; P = .007). No between-group differences were found in 60-day mortality (10% [2 of 21] for OVP versus 7% [2 of 29] for NOVP; P > 0.999). OVP appears to be safe and effective for secondary prevention of CDI in the HSCT/HM population. Prospective trials are needed to validate the effectiveness of OVP in this vulnerable population to prevent rCDI.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN and DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "seesaw effect," where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.

Patient: Male, 78 Final Diagnosis: Right thalamic intraparenchymal hemorrhage with intraventricular extension Symptoms: Altered mental status • left sided weakness Medication: Levetiracetam Clinical Procedure: Continuous renal replacement therapy Specialty: Critical Care Medicine Objective: Unusual or unexpected effect of treatment Background: Levetiracetam is an antiepileptic drug frequently used in critically ill patients. Levetiracetam is primarily eliminated as a parent compound via glomerular filtration and requires dose adjustment in renal insufficiency, but the literature on patients receiving continuous veno-venous hemofiltration (CVVH) is scant. Case Report: We report the levetiracetam pharmacokinetic profile of a patient being treated with levetiracetam 1000 mg intravenously every 12 h who required continuous veno-venous hemofiltration (CVVH). The patient underwent CVVH utilizing a high-flux polyethersulfone membrane filter. The blood flow rate was 250 ml/min, and the predilution replacement therapy fluid flow rate was 2000 ml/h. After achieving presumed steady-state on levetiracetam 1000 mg q12h, serial plasma samples (pre- and post-filter) and effluent samples were drawn at 2, 4, 6, 8, and 10 h. Levetiracetam concentrations were determined utilizing LC-MS/MS. The levetiracetam maximum concentration (Cmax), minimum concentration (Cmin), half-life, area under the concentration-time curve (AUC0–12), clearance (CL), and volume of distribution (Vd) were 30.7 μg/ml, 16.1 μg/ml, 12.9 h, 272 mg·hr/L, 3.68 L/h, and 0.73 L/kg, respectively. The sieving coefficient was 1.03±0.08. CVVH represented 61.3% of the total levetiracetam clearance. The patient was maintained on CVVH for 24 consecutive days and then transitioned to intermittent hemodialysis and remained seizure-free. Conclusions: CVVH is highly effective in removing levetiracetam from circulating plasma. Due to the effective removal, standard doses of levetiracetam are required to maintain adequate plasma concentrations. Dose reductions utilizing HD or estimated creatinine clearance recommendations will likely lead to subtherapeutic levels, especially if higher CVVH flow rates are used.

Background Few published studies exist to describe the off-label use of multiple-dose fosfomycin for outpatient treatment of complicated urinary tract infections (UTI). The purpose of this study was to characterize the patients, infections, drug susceptibilities, and outcomes of multiple-dose fosfomycin episodes for outpatient UTI treatment. Methods This retrospective study evaluated patients who received an outpatient prescription for multiple-dose fosfomycin between July 1999 and June 2018. Multiple-dose fosfomycin prescriptions dispensed for UTI prophylaxis were excluded. The primary outcome was clinical resolution (complete resolution of signs and symptoms) of infection within 30 days. Secondary outcomes included descriptions of antibiotics and cultures before and after treatment, 30-day bacteriologic resolution (posttreatment urine culture, In this retrospective cohort study assessing 171 multiple-dose fosfomycin treatment episodes for complicated UTI, the most common regimen was 1 dose every 3 days for 3 doses. Thirty-day clinical and bacteriological resolution rates were 66.1% and 47.8%, respectively.

The objective of this study was to determine the pharmacokinetics and pharmacodynamics (PK/PD) of a weight-based cefoxitin dosing regimen for surgical prophylaxis in obese patients. Patients received a single dose of cefoxitin at 40 mg/kg based on total body weight. Cefoxitin samples were obtained over 3 h from serum and adipose tissue, and concentrations were determined by validated high-performance liquid chromatography. Noncompartmental pharmacokinetic analysis was performed, followed by Monte Carlo simulations to estimate probability of target attainment (PTA) for Staphylococcus aureus , Escherichia coli , and Bacteroides fragilis over 4-h periods postdose. Thirty patients undergoing bariatric procedures were enrolled. The body mass index (mean ± standard deviation [SD])was 45.9 ± 8.0 kg/m 2 (range, 35.0 to 76.7 kg/m 2 ); the median cefoxitin dose was 5 g (range, 4.0 to 7.5 g). The mean maximum concentrations were 216.15 ± 41.80 μg/ml in serum and 12.62 ± 5.89 in tissue; the mean tissue/serum ratio was 8% ± 3%. In serum, weight-based regimens achieved ≥90% PTA (goal time during which free [unbound] drug concentrations exceed pathogen MICs [ f T>MIC] of 100%) for E. coli and S. aureus over 2 h and for B. fragilis over 1 h; in tissue this regimen failed to achieve goal PTA at any time point. The 40-mg/kg regimens achieved higher PTAs over longer periods in both serum and tissue than did the standard 2-g doses. However, although weight-based cefoxitin regimens were better than fixed doses, achievement of desired pharmacodynamic targets was suboptimal in both serum and tissue. Alternative dosing regimens and agents should be explored in order to achieve more favorable antibiotic performance during surgical prophylaxis in obese patients.

Background Predictive scoring systems, such as the Pitt Bacteremia Score (PBS) and Acute Physiology and Chronic Health Evaluation II (APACHE-II), can optimize clinical decisions and provide adjustment for confounding among patients with Methicillin-Resistant Staphylococcus aureus bacteremia (MRSAB). The recently introduced MRSAB score demonstrated superior discriminatory ability in mortality prediction compared to APACHE-II and PBS, however external validation is lacking. Methods Single center, retrospective cohort study of adult patients admitted to University of Colorado Hospital from 2013–2020 with initial episode of MRSAB were included. Patients transferred from an outside hospital, left against medical advice, or died/pursued comfort care within 24 hours of index culture were excluded. The primary outcome was discrimination of 30-day all-cause mortality. The discriminatory abilities of APACHE-II, PBS and MRSAB were compared using receiver operating characteristic (ROC) analysis. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were analyzed, and optimal MRSAB score was identified by Youden Index. Results Overall, 170 patients met study inclusion. The median (IQR) age was 57 (47-66) years, 69% were male, and 19% were in an ICU during blood culture collection. The most common infection sites were skin and soft tissue (41%), musculoskeletal (23%), and line-related (19%), whereas endovascular (14%) infections were less common. The median (IQR) PBS, APACHE-II and MRSAB scores were 2 (0-4),17 (12-23), and 6.5 (3-11), respectively. Thirty-day all-cause mortality was 12.9%. ROC curve analysis revealed an area (95% CI) for the APACHE-II, PBS, and MRSAB scores of 0.84 (0.77-0.92), 0.71 (0.57-0.85), 0.79 (0.68-0.90), respectively. A threshold MRSAB score of ≥10 was identified, whereby mortality was 3.6% with MRSAB < 10, and 30% with MRSAB ≥10. A MRSAB ≥10 had a sensitivity, specificity, PPV and NPV with corresponding 95% CIs of 0.82 (0.63-0.94), 0.72 (0.68-0.79), 0.30(0.19-0.42) and 0.96(0.92-0.99), respectively. Receiver operator characteristic (ROC) curves for the prediction of 30-day mortality Conclusion The MRSAB score is a useful predictive scoring model, with discriminatory ability comparable to APACHE-II, and excellent NPV at ≥10. Our findings support routine clinical and research application. Disclosures matthew miller, PharmD, Allergan (Speaker’s Bureau)Tetraphase (Speaker’s Bureau)

Neurocritically ill patients have clinically significant alterations in pharmacokinetic parameters of renally eliminated medications that may result in subtherapeutic plasma and cerebrospinal fluid antibiotic concentrations.We conducted a prospective randomized open-label study of adult neurocritically ill patients treated with vancomycin and cefepime. Vancomycin 15 mg/kg and cefepime 2 g were dosed at every-8- or 12-hour intervals. The primary outcomes were the achievement of pharmacodynamic (PD) targets related to time of unbound drug above minimum inhibitory concentrations (MIC) for 60% or more of the dosing interval (fT MIC ≥ 60%) for β-lactams and ratio of 24-hour area under the curve (AUC):MIC of 400 or greater for vancomycin.Twenty patients were included in the study. They were divided equally between the every-12-hour and every-8-hour dosing groups. Patients (mean age 51.8 ± 11 yrs) were primarily male (60%) and white (95%), and most had an admission diagnosis of intracranial hemorrhage (80%). Compared with the every-12-hour group, the every-8-hour vancomycin group achieved target trough concentrations (higher than 15 μg/ml) significantly more frequently at initial measurement (0% vs 80%, p0.01) and at 7-10 days (0% vs 90%, p=0.045) and achieved PD targets more frequently at increasing MICs. Similarly, compared with every-12-hour dosing, the every-8-hour cefepime dosing strategy significantly increased PD target attainment (fT MIC ≥ 60%) at an MIC of 8 μg/ml (20% vs 70%, p=0.02).This study demonstrated that more frequent dosing of vancomycin and cefepime is required to achieve optimal PD targets in adult neurocritically ill patients. The need for increased total daily doses is potentially secondary to the development of augmented renal clearance.

Background: Methicillin-susceptible Staphylococcus aureus (MSSA) is a frequent cause of bloodstream infections (BSI). Treatment with nafcillin (NAF) has been preferred to cefazolin (CFZ). However, comparable outcomes have been found with CFZ with possibly lower risk for side-effects. This study compared safety and effectiveness of NAF versus CFZ for MSSA BSI. Methods: This single center retrospective study evaluated adults admitted with MSSA BSI who received NAF or CFZ. Patients receiving ≥24 h of antibiotics were included for safety analyses. Patients receiving NAF or CFZ for ≥75% of a 14 day minimum treatment course were assessed for clinical effectiveness. The primary safety outcome was incidence of renal toxicity with multiple secondary safety endpoints. Clinical success was defined as symptom resolution, repeat negative cultures, lack of additional therapy for presumed failure, and lack of recurrence within 30 days. Results: A total of 130 patients receiving NAF (n = 79) or CFZ (n = 51) were included for safety analysis. Of those, 90 met criteria for effectiveness assessment (NAF n = 40, CFZ n = 50). Baseline characteristics were well matched. NAF was associated with a higher incidence of nephrotoxicity compared to CFZ (25% vs. 2%, RR 1.31, 95% CI 1.15–1.5, p

Critically ill and immunocompromised patients, particularly within the transplant and human immunodeficiency virus (HIV)-infected populations, are at higher risk for severe viral infections such as those caused by cytomegalovirus (CMV), adenovirus, and disseminated herpes simplex virus (HSV). Infection with hepatitis C virus (HCV) is common, and many new antiviral regimens have come into use for management of infected patients. Influenza continues to be a significant public and global health problem as well. Many of the currently available antiviral agents have been in clinical use for many years, and clinically significant drug interactions are reasonably well characterized, while interaction data are often unavailable for newer antiretroviral and immunosuppressant agents. Some of the non-HIV antiviral drugs such as acyclovir, famciclovir, oseltamivir, and amantadine are associated with relatively few clinically significant drug interactions. However, there are a number of significant interactions which must be considered for the safe and effective use of drugs such as ganciclovir, foscarnet, cidofovir, ribavirin, and the interferons. This chapter summarizes available data regarding pharmacokinetic and toxic interactions with the current antiviral agents, excluding those used specifically for HIV infections as well as the newer direct-acting antiviral (DAA) drugs for HCV.

SummaryWhat is known and objective Practices vary between institutions and amongst prescribers regarding when to initiate stress ulcer prophylaxis (SUP), which agent to choose (including doses and frequencies) and rationale, and decisions about escalation or discontinuation of therapy. The purpose of this survey is to evaluate the perceptions of prescribers about risk assessment of stress-related mucosal bleeding (SRMB) and practice patterns of SUP. Methods A cross-sectional survey of 800 US critical care prescribers using the membership of the Society of Critical Care Medicine. The levels of agreement with specific statements were rated on a nine-point Likert scale. Results Of 712 eligible recipients, 245 (34·4%) completed the questionnaire. Respondents were primarily attending physicians (81·2%) working in adult medical or surgical (59·2%) intensive care units. Mucosal ischaemia was identified as the pathophysiological cause of SRMB by 110 (44·9%) respondents. Respondents agreed that risk factors for SRMB were acute hepatic failure, anticoagulant use, burns >35%, coagulopathy, absence of enteral feeding, recent gastroduodenal ulcer, corticosteroid use, Helicobacter pylori infection, neurologic injury, trauma, NSAID use, mechanical ventilation, shock and sepsis. Histamine subtype 2 receptor antagonists (58·4%) and proton pump inhibitors (39·6%) were the most frequently chosen agents. No consensus was reached about whether either class is associated with clostridium difficile infection or nosocomial pneumonia. Reasons to discontinue therapy included clinically improved patient status (73·1%), extubation (68·2%), reversal of ‘nil-by-mouth’ (68·6%) and transfer to a non-ICU setting (67·8%). What is new and conclusions Considerable variability exists in the perceptions surrounding risk factors for SRMB and prescribing patterns for SUP therapy likely because limited or conflicting data are available addressing these issues. Opportunities exist to educate prescribers and conduct research about the pathologic cause and risk factors for SRMB, the preferred class of agents, and the appropriate discontinuation of therapy.

Objectives This study was undertaken to identify a preferred dosing strategy for patients undergoing coronary artery bypass grafting or valve replacement procedures with cardiopulmonary bypass. Methods Patients undergoing coronary artery bypass grafting, valve replacement surgery, or both were randomly assigned to receive either standard 1-g dosing with vancomycin before and after cardiopulmonary bypass or a single weight-based 20-mg/kg dose before surgery. The primary outcome was the percentage of time plasma concentrations were greater than 15 μg/mL during cardiopulmonary bypass and at surgical closure. Secondary outcomes included concentration of vancomycin in endothoracic tissue after vancomycin infusion, average time patients had vancomycin concentrations greater than 15 μg/mL, and vancomycin plasma and tissue pharmacokinetic parameters. Results Baseline characteristics were similar between the study dosing group (n = 10) and the standard dosing group (n = 10). From postinfusion to end of bypass, the median percentage of time vancomycin concentrations remained greater than 15 μg/mL was 100% (interquartile range [IQR], 72.6%-100%) for weight-based dosing versus 43.7% (IQR, 28.7%-53.4%) for standard dosing ( P = .0005). From postinfusion to surgical closure, the percentage of time vancomycin concentrations remained greater than 15 μg/mL was significantly higher in the weight-based group (100% [IQR, 58.3%-100%] vs 34.6% [IQR, 25.3%-41.6%]; P = .0005). Weight-based dosing increased calculated time with vancomycin concentrations greater than 15 μg/mL and resulted in higher endothoracic tissue vancomycin concentrations. Conclusions Weight-based vancomycin dosing before coronary artery bypass grafting or valve replacement results in vancomycin concentrations greater than 15 μg/mL consistently more than does standard 1-g dosing.

Everolimus (EVR) has inter-individual pharmacokinetic (PK) variability and a narrow therapeutic index. The study objective was to determine whether genetic polymorphisms, co-medications, and/or demographic variables accounted for inter-individual variability in EVR PK in lung transplant recipients (LTxR). LTxR were genotyped for ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T, CYP3A4*1B, CYP3A5*3, CYP2C8*2/*3/*4, and pregnane X receptor (NR1I2) c.44477T>C, c.63396C>T, c.69789A>G polymorphisms. The primary outcome was the difference in dose-adjusted EVR levels (EVR L/D) between ABCB1 diplotype groups (2 vs. 1 vs. 0 copies of the 1236C/2677G/3435C haplotype). Sixty-five LTxR were included. There was no significant difference in EVR L/D between ABCB1 CGC diplotype groups (CGC/CGC = 2.4 ± 1.1 [n = 9] vs. CGC/XXX = 2.5 ± 1.7 [n = 36] vs. XXX/XXX = 2.7 ± 1.7 ng/mL per mg/d [n = 20]; p = 0.9). CYP3A5*3, CYP3A4*1B, CYP2C8*3/*4, and NR1I2 polymorphisms were not associated with EVR L/D. EVR L/D was 3.4 ± 1.7 in LTxR receiving diltiazem (DILT) vs. 1.8 ± 1.1 ng/mL per mg/d in LTxR not receiving DILT (p

Background Tedizolid is an oxazolidinone antibiotic with broad-spectrum Gram-positive activity approved for the treatment of skin and skin structure infections with a 6-day course. Oxazolidinone antibiotics represent appealing options for prolonged antimicrobial therapy due to their available oral formulations with excellent bioavailability and potent in vitro activity against various multidrug-resistant Gram-positive organisms, Mycobacterium spp., and Nocardia spp. Although tedizolid and linezolid offer a similar clinical spectrum based on antimicrobial activity alone, long-term use of linezolid is often limited by serious adverse effects. Preliminary assessments have suggested better tolerability with tedizolid; however, these are limited by shorter exposure duration. The objective of this study was to evaluate the long-term safety and tolerability of tedizolid. Methods Retrospective cohort of adult patients receiving tedizolid for ≥ 28 days, with baseline complete blood cell (CBC) indices available, and CBC indices drawn ≥ 14 days into tedizolid course. The primary objective was to evaluate the long-term tolerability of tedizolid. Results 13 patients met inclusion criteria: median age 61 years (IQR, 51–64 years), 69% male, 85% Caucasian. The majority of patients utilized tedizolid for suppression (85%), and the median duration of tedizolid was 113 days (IQR, 71–204 days). There were no differences in CBC indices when comparing baseline to last laboratory draw throughout tedizolid exposure: platelets (baseline: 203 x 109/L (IQR, 186–283 x 109/L) vs. last: 196 x 109/L (IQR, 161–303 x 109/L; p = 0.65), hemoglobin (baseline: 9.8 g/dL (IQR, 8.8–11.1 g/dL) vs. last: 11.7 g/dL (IQR, 11.0–13.1 g/dL; p = 0.10), and white blood cells (baseline: 6.2 x 109/L (IQR, 5.6–7.6 x 109/L) vs. last: 6.5 x 109/L (IQR, 6.3–7.3 x 109/L; p = 0.45). The final laboratory draws were obtained a median of 78 days (IQR, 44–119 days) into therapy. No patients experienced peripheral neuropathy, optic neuritis/visual changes, or serotonin syndrome during treatment/suppression with tedizolid during the period evaluated. Conclusion Long-term therapy with tedizolid appears to be well-tolerated. Treatment and suppression with tedizolid seems to be a safe alternative to linezolid. Disclosures All authors: No reported disclosures.

Background Appropriate application of antimicrobial PK/PD properties is crucial to optimizing patient outcomes. Although β-lactams are among the most utilized and effective antibiotics, optimal dosing strategies in obese populations are largely unknown. The objective of this study was to compare PK/PD of CPM in non-obese (NO, weight 80–100 kg) and obese (O, weight > 100 kg) patients. Methods A prospective comparative PK/PD analysis was conducted in NO and O patients receiving CPM. Blood samples were obtained at 30, 60, 120, 240, 360, and 480 minutes after CPM infusion. CPM concentrations were determined by reversed-phase high-performance liquid chromatography. Non-compartmental PK analyses were performed, followed by Monte Carlo simulations (Oracle Crystal Ball®, 5,000 simulated patients) to estimate probability of target attainment (PTA) against common Gram-negative pathogens. The desired PD target for CPM was % time above MIC of unbound drug (%fT > MIC) ≥ 60%. Chi-squared and Mann–Whitney U tests were used for analysis. Results Seventeen patients were enrolled and most (94%) received CPM 2 g q8h. A significant difference in actual body weight and body mass index was observed (P < 0.001). There were no differences in other baseline or PK characteristics between the two groups. Utilizing CPM 2 g q8h, PTA ≥ 90% was not observed for organisms with an MIC of 8 μg/mL, the current CLSI breakpoint for P. aeruginosa and A. baumannii (PTA = 88% vs. 81% in NO and O groups, respectively). With a 6 g continuous infusion (CI), however, ≥ 90% PTA was achieved in both groups (PTA = 100%) for organisms with an MIC of 8 μg/mL, while a regimen of 2 g q8h (infused over 3 hours [EI]) also provided PTA of ≥ 90% in both groups (PTA = 98% vs. 92% in NO and O groups, respectively). Goal PTA was not obtained in either group for organisms with an MIC of 4 μg/mL with CPM 1 g q8h or 2 g q12h (i.e., CLSI recommended dosing for organisms with MICs of 4 μg/mL). Conclusion Optimizing PK/PD parameters through novel dosing strategies are essential in both the NO and O populations for optimal CPM exposure in susceptible pathogens with higher MICs. CPM 6 grams/day by either CI or EI provides more optimal PK/PD characteristics in obese patients for pathogens with MICs at or near the current CLSI-recommended breakpoint. Disclosures All authors: No reported disclosures.

While the canonical function of somatostatin (SST) is to inhibit the secretion of growth hormone, it has a number of other physiologic effects that are less widely appreciated. Octreotide, an analog of SST, is not uncommonly used in the critical care setting, particularly for the treatment of variceal hemorrhage. Herein, we discuss the biology and pharmacology of SST, octreotide, and other SST analogs. We also review the evidence behind their use in esophageal variceal bleeds, hepatorenal syndrome, hypoglycemia due to sulfonylurea poisoning, and chylous pleural effusions.

Introduction: Sedation with dexmedetomidine may facilitate ventilator liberation and limit the occurrence of delirium. No trial has assessed patient recall or the development of psychological outcomes after dexmedetomidine sedation. This pilot study evaluated whether transitioning benzodiazepine sedation to dexmedetomidine alters patient recall and the incidence of anxiety, depression, or acute stress disorder (ASD). Methods: This investigation was a randomized, double-blind, single-center study. Existing continuous benzodiazepine sedation was converted to dexmedetomidine or midazolam when patients qualified for daily awakenings. Sedation was titrated to achieve Riker sedation agitation scores of 3 to 4. The intensive care unit (ICU) Stressful Experiences Questionnaire, hospital anxiety and depression scale, and the impact of event scale-revised were administered before hospital discharge to assess recall, anxiety, depression, and manifestations of ASD. Results: A total of 11 patients received dexmedetomidine, and 12 patients received midazolam. Median dosing was 0.61 µg/kg/h for 3.5 days for dexmedetomidine and 3.7 mg/h for 3 days for midazolam. Attainment of goal sedation and analgesia was similar; however, more dexmedetomidine patients experienced agitation and pain. The median duration of mechanical ventilation from study drug initiation to extubation was 3.4 days in dexmedetomidine patients and 2.9 days in midazolam patients. Dexmedetomidine patients remembered 18.5 experiences compared with 8.5 in midazolam patients ( P = .015). Rates of anxiety and depression were similar. In all, 5 (62.5%) dexmedetomidine patients and 1 (12.5%) midazolam patient manifested ASD ( P = .063), and 1 dexmedetomidine patient and 5 midazolam patients developed new-onset delirium ( P = .07). Hypotension occurred in 10 (90.9%) dexmedotomidine patients and 6 (50%) midazolam patients ( P = .069). Conclusions: Transitioning benzodiazepine sedation to dexmedetomidine when patients qualify for daily awakenings may reduce the development of delirium and facilitate remembrance of ICU experiences but may lead to manifestations of ASD. Monitoring hypotension is required for both the sedatives. Additional comparative studies focusing on the long-term impact of ICU recall and psychological outcomes are needed.

Study Objective To evaluate the steady-state pharmacokinetic and pharmacodynamic parameters of piperacillin in morbidly obese, surgical intensive care patients. Design Open-label single-center prospective study. Setting Level I trauma center and university-affiliated teaching institution. Patients Nine morbidly obese (body mass index [BMI] 40.0 kg/m2 or higher) hospitalized patients admitted to the trauma and surgical intensive care service who were treated with piperacillin-tazobactam between December 15, 2010, and April 18, 2012. Intervention Patients received intravenous piperacillin-tazobactam 4.5 g every 6 hours, administered as a 30-minute infusion. Measurements and Main Results Patients' blood samples were collected after the administration of the fourth, fifth, or sixth dose (i.e., at steady state). Serum piperacillin concentrations were determined by using a validated high-performance liquid chromatography assay; these concentrations were used to estimate pharmacokinetic parameters, and 5000-patient Monte Carlo simulations were performed. The probability of target attainment for 50% or higher of the dosing interval during which free (unbound) drug concentrations exceeded the minimum inhibitory concentration (%fT > MIC) of likely pathogens was calculated for piperacillin at various MICs. Patient demographic and clinical characteristics included a mean ± SD total body weight of 164 ± 50 kg, BMI of 57 ± 15.3 kg/m2, and age 57 ± 11 years, and a median Acute Physiology and Chronic Health Evaluation II score of 22 (interquartile range 21–26). Compared with values previously reported in other populations, the volume of distribution was increased in the study patients, and total system clearance was decreased. The net result was a mean ± SD half-life of 3.7 ± 1.2 hours compared with ~1 hour reported in other populations. This contributed to an extended %fT > MIC for likely pathogens. Results from all nine patients showed %fT > MIC of 100% at the susceptibility breakpoint MIC of 16 mg/L and 85% or higher at an MIC of 32 mg/L. Conclusion The pharmacokinetics of piperacillin is altered in morbidly obese, surgical intensive care patients. The use of standard-dosage piperacillin-tazobactam 4.5 g intravenously every 6 hours was shown to be an appropriate dosage for this study population.

Objectives HIV-infected patients are commonly prescribed several medications and are thus at risk for drug interactions that may result in QTc prolongation. We sought (1) to identify the frequency of electrocardiogram (ECG) monitoring (2), to determine the prevalence of drug interactions involving QTc-prolonging medications, and (3) to quantify the prevalence of QTc prolongation. Methods A cross-sectional study was conducted among HIV-infected adults. Demographics, medications, drug interactions and comorbidities were abstracted from patients' medical records. Abnormal QTc interval was defined per the UK Committee for Proprietary Medicinal Products. Clinical characteristics were compared among ECG recipients and nonrecipients. Among ECG recipients, the prevalence and predictors of QTc prolongation were assessed. Results Among the 454 patients included in the study, 80.8% were prescribed a medication associated with QTc prolongation and 39% had drug interactions expected to increase QTc prolongation risk. There were 138 patients (30.3%) who received ECG testing. Receipt of ECG monitoring was associated with increasing age, diabetes, increasing total number of medications and gastroesophageal reflux disease. Among ECG recipients, the prevalence of abnormal QTc interval was 27.5%. Chronic kidney disease [prevalence ratio (PR) 3.47; 95% confidence interval (CI) 1.37–8.83; P = 0.009], hepatitis C virus coinfection (PR 2.26; 95% CI 0.97–5.27; P = 0.06) and hypertension (PR 2.11; 95% CI 0.93–4.81; P = 0.07) were independently associated with an abnormal QTc interval. Conclusions A low frequency of ECG testing was observed, despite a high use of medications associated with QTc prolongation. The risk of abnormal QTc interval was highest among patients with chronic kidney disease, hypertension and hepatitis C virus coinfection.

These guidelines were developed jointly by the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Surgical Infection Society (SIS), and the Society for Healthcare Epidemiology of America (SHEA). This work represents an update to the

Surgical-site infections are the leading cause of post-operative morbidity and mortality as well as increased costs following colorectal surgery. The purpose of this study was to evaluate different β-lactam antimicrobial dosing regimens currently used for prophylaxis in elective colorectal procedures with the aim of identifying optimal antibiotics and dosing regimens. Serum pharmacokinetic (PK) parameters specific to each drug for use in pharmacodynamic (PD) modelling were obtained from the published literature. Susceptibility data for Escherichia coli , Bacteroides fragilis and Staphylococcus aureus for use in modelling simulations were obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Monte Carlo simulation was used to evaluate the influence of dose and dosing frequency of tested antibiotics to achieve a prophylaxis target fT >MIC (time during which the free drug concentration exceeds the pathogen minimum inhibitory concentration) of 100% for up to 4h. Ertapenem 1g, cefuroxime 1.5g and cefazolin 2g were the only antibiotic regimens that consistently yielded target fT >MIC of 100% for the entire 4-h post-dose interval and against all targeted organisms more than 90% of the time. In contrast, cefoxitin, cefotetan and ampicillin/sulbactam yielded very poor predicted PK/PD performances. In conclusion, this study demonstrates the value of, and need for, applied PD research in the area of surgical prophylaxis. Whether cefoxitin, cefotetan or ampicillin/sulbactam should continue to be advocated as first-line agents for prophylaxis during elective colorectal surgery, particularly at the standard doses currently being used, is debatable.

Unfractionated heparin (UFH) is a frequently utilized indirect anticoagulant that induces therapeutic effect by enhancing antithrombin (AT)-mediated procoagulant enzyme inhibition. In suspected heparin resistance (HR) during cardiopulmonary bypass, AT activity may be decreased and AT supplementation helps restore UFH responsiveness. The benefit of AT supplementation in HR over longer durations of UFH therapy is unclear. The objective of this study was to describe and evaluate the use of AT III concentrate in the intensive care units (ICUs) at our institution for improving UFH therapy response over 72 hours. A total of 44 critically ill patients were included in the analysis—22 patients received at least 1 dose of AT and 22 patients received no AT. Thirty (68.2%) of the 44 patients were receiving mechanical circulatory support. Baseline characteristics were similar between groups. The average AT activity prior to AT supplementation was 57.9% in the treatment group, and the median cumulative dose of AT was 786.5 U (9.26 U/kg) per patient. There were no significant differences observed in proportion of time spent in therapeutic range (31.9% vs 35.2%, P = .65), time to therapeutic goal (16.5 vs 15.5 hours, P = .97), or patients who experienced a bleeding event (5 vs 5, P = .99) between groups. In conclusion, AT supplementation had minimal impact on anticoagulant response in this cohort of ICU patients with mild to moderate HR receiving a prolonged UFH infusion. Additional research is needed to define AT activity targets and to standardize AT supplementation practices in patients receiving prolonged heparin infusion.

Purpose: This study evaluated thiocyanate concentrations and factors associated with thiocyanate accumulation in intensive care unit patients receiving nitroprusside with and without sodium thiosulfate coadministration. Materials and Methods: This retrospective study evaluated critically ill adults who received nitroprusside infusions and had at least one thiocyanate concentration. Patients with thiocyanate accumulation (concentrations ≥30 µg/mL) were compared to patients without accumulation. Factors associated with accumulation were determined by Spearman correlation and multivariate regression. Results: Thiocyanate concentrations (n = 192) were obtained from 87 patients. Fourteen of the 87 (16%) patients experienced thiocyanate accumulation with a mean (SD) thiocyanate concentration of 44 ± 11 µg/mL. Patients with accumulation had received greater cumulative nitroprusside doses (28 vs 8.2 mg/kg, P < .01), greater cumulative sodium thiosulfate doses (16.8 vs 10.1 mg/kg, P < .01), and longer infusion durations (10.9 vs 6.0 days, P < .01), compared to patients without accumulation. Sodium thiosulfate coadministration resulted in greater thiocyanate concentrations (22.8 ± 16.7 vs 16.8 ± 14.9 μg/mL, P = .01), despite utilization of lower cumulative nitroprusside doses (10.2 vs 14.6 mg/kg, P = .03). Cumulative nitroprusside dose ( r2 .44, P < .001) and cumulative sodium thiosulfate dose ( r2 .32, P < .001) demonstrated a significant correlation with measured thiocyanate concentrations. Thiocyanate accumulation was independently associated with cumulative nitroprusside dose in mg/kg (regression coefficient 0.75, 95% CI 0.63-0.89; P < .01). No clinically significant adverse effects of cyanide or thiocyanate toxicity were observed. Conclusions: Cumulative nitroprusside dose was independently associated with thiocyanate accumulation. Despite elevated thiocyanate levels in 16% of patients, there was no clinical evidence of cyanide or thiocyanate toxicity. Routine monitoring of thiocyanate concentrations appears most warranted in patients receiving higher cumulative doses of nitroprusside.

Objective Determine whether a comprehensive approach to implementing national consensus guidelines for nursing home–acquired pneumonia (NHAP) affected hospitalization rates. Design Quasi-experimental, mixed-methods, multifaceted, unblinded intervention trial. Setting Sixteen nursing homes (NHs) from 1 corporation: 8 in metropolitan Denver, CO; 8 in Kansas and Missouri during 3 influenza seasons, October to April 2004 to 2007. Participants Residents with 2 or more signs and symptoms of systemic lower respiratory tract infection (LRTI); NH staff and physicians were eligible. Intervention Multifaceted, including academic detailing to clinicians, within-facility nurse change agent, financial incentives, and nursing education. Measurements Subjects' NH medical records were reviewed for resident characteristics, disease severity, and care processes. Bivariate analysis compared hospitalization rates for subjects with stable and unstable vital signs between intervention and control NHs and time periods. Qualitative interviews were analyzed using content coding. Results Hospitalization rates for stable residents in both NH groups remained low throughout the study. Few critically ill subjects in the intervention NHs were hospitalized in either the baseline or intervention period. In control NHs, 8.7% of subjects with unstable vital signs were hospitalized during the baseline and 33% in intervention year 2, but the difference was not statistically significant ( P = .10). Interviews with nursing staff and leadership confirmed there were significant pressures for, and enablers of, avoiding hospitalization for treatment of acute infections. Conclusions Secular pressures to avoid hospitalization and the challenges of reaching NH physicians via academic detailing are likely responsible for the lack of intervention effect on hospitalization rates for critically ill NH residents.

Appropriate dosing of antifungal drugs is crucial to achieving favorable outcomes in patients with invasive fungal infections. The use of various types of renal replacement therapy (RRT) in patients with severe acute or chronic renal insufficiency adds another level of complexity to the already challenging use of these drugs. The medical literature provides only a limited number of studies specifically addressing the use of antifungal agents in patients receiving RRT, and there are a number of inherent difficulties in interpreting and applying these studies of drug dosing during RRT to individual patients. This article briefly reviews recent studies examining the dosing of antifungal agents during RRT, and also briefly reviews device-related and drug-related factors that determine the removal of drugs during RRT. Finally, this article summarizes current recommendations for dosing of antifungal agents in patients receiving RRT and highlights areas for future study.

Study Objective. To evaluate the safety and efficacy of bivalirudin compared with heparin for preventing hemofilter occlusion during continuous venovenous hemofiltration (CVVH). Design. Prospective, randomized, double-blind study. Setting. University-affiliated hospital. Patients. Ten critically ill adults (median age 58 yrs, 70% male) with acute renal failure who, without anticoagulation, experienced hemofilter survival time of 24 hours or less during CVVH. Intervention. Patients were randomized to receive bivalirudin 2 mg/hour (five patients) or heparin 400 units/hour (five patients) administered prefilter into the extracorporeal circuit. Measurements and Main Results. Patients had a median Acute Physiology and Chronic Health Evaluation (APACHE) II score of 24, Sequential Organ Failure Assessment (SOFA) score of 11, and reduced antithrombin activity (75.5 units/dl). Baseline characteristics were not significantly different between groups. Study drug was administered in 40 hemofilters (18 from bivalirudin-treated patients, 22 from heparin-treated patients). The primary efficacy outcome was hemofilter survival time, defined as the interval of time between commencement of CVVH with a new extracorporeal circuit (hemofilter) and hemofilter failure. Compared with no anticoagulation, the addition of bivalirudin or heparin significantly improved hemofilter survival time (mean ± SD 10 ± 5 hrs with no anticoagulation vs 22 ± 18 hrs with anticoagulation, p=0.0005). Hemofilter survival time was significantly increased in patients receiving bivalirudin versus those receiving heparin (29.6 ± 20.7 vs 16.5 ± 13.6 hrs, p=0.045). Independent predictors of hemofilter survival were use of bivalirudin therapy and increased antithrombin III activity. No patients randomized to bivalirudin experienced any bleeding or thrombosis events; one patient who received heparin developed alveolar hemorrhage, and one developed a lower extremity deep vein thrombosis. Conclusion. Compared with heparin, bivalirudin was more efficacious in prolonging hemofilter survival time and was well tolerated. Additional studies of bivalirudin for prevention of hemofilter occlusion during continuous renal replacement therapy are warranted.

Study Objective. To determine if increased expression of efflux pumps, mutations in the genes encoding regulatory proteins for efflux pumps, or the combination is associated with multidrug-resistant (MDR) Pseudomonas aeruginosa isolates. Design. Microbiologic evaluation of prospectively collected Pseudomonas aeruginosa isolates. Setting. University teaching hospital. Isolates. One hundred eight unique P. aeruginosa isolates—50 non-MDR and 58 MDR isolates—obtained from pulmonary or blood sources from patients admitted to the intensive care unit between January 1, 1999, and December 31, 2004. Measurements and Main Results. Isolates were considered MDR if they were resistant to at least three of the following four drugs: ciprofloxacin, tobramycin, ceftazidime, or imipenem. Possible mutations in efflux regulatory genes mexR, nfxB, and mexZ were analyzed by using polymerase chain reaction amplification and DNA sequencing. Determination of the expression of outer membrane proteins OprM and OprJ was performed by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblotting. Differences in regulatory gene mutations and outer membrane protein expression were compared between non-MDR and MDR isolates. Among the 108 P. aeruginosa isolates, the MDR isolates were more likely to overexpress OprM compared with non-MDR isolates (64% vs 2%, p

Objective: To describe a case of successful bivalirudin use as a prefilter anticoagulant in continuous venovenous hemofiltration (CVVH). Case Summary: A 30-year-old male was brought to the hospital by ambulance with an anterior communicating artery subarachnoid hemorrhage, signs of intraparenchymal hemorrhage, and hydrocephalus. During the patient's complicated hospital course, he developed acute renal failure requiring CVVH, as well as hepatic insufficiency (Child-Pugh class B). Unfractionated heparin was used as a prefilter anticoagulant. After he had a positive heparin-induced thrombocytopenia (HIT) antibody test, prefilter heparin was discontinued in favor of bivalirudin. Filter survival and systemic activated partial thromboplastin time (aPTT) values were compared between prefilter heparin (n = 5) and bivalirudin (n = 4). Filter survival was similar (median 26 h with heparin vs 37 h with bivalirudin; p = 0.52). Prefilter bivalirudin 1–2.5 mg/hour (0.009–0.023 mg/kg/h) was effective in maintaining systemic aPTTs that were 1–1.4 times the reference range. Serotonin release assay and subsequent HIT antibodies were negative. The patient's renal function improved and CVVH was discontinued. Discussion: Critically ill patients requiring CVVH often need regional or systemic anticoagulation to prevent filter occlusion. In some patient populations, such as those with HIT or liver failure, prefilter heparin and regional citrate, respectively, may not be options. Alternative anticoagulants may be needed to avoid complications of frequent filter occlusions. The direct thrombin inhibitors (DTIs) lepirudin and argatroban have been used to maintain hemofilter patency, in small studies. Bivalirudin may have pharmacokinetic advantages over other DTIs when used in patients with hepatic and renal impairment. In our patient, bivalirudin provided a safe alternative to heparin therapy and was effective in maintaining hemofilter patency during CVVH. Conclusions: Prefilter bivalirudin may be an option to prevent filter occlusion in patients requiring continuous renal replacement therapy. Future studies are needed to validate the safety and efficacy of bivalirudin as a prefilter anticoagulant.

Purpose To determine the vitreous penetration of penciclovir (Denavir; GlaxoSmithKline, Philadelphia, Pennsylvania, USA) after oral administration of the prodrug famciclovir (Famvir; Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA). Design Prospective interventional case series. Methods Ten patients undergoing elective pars plana vitrectomy at a single institution were enrolled to take 3 oral doses of famciclovir 500 mg the day preceding surgery and a fourth dose on the morning of surgery. Blood and undiluted vitreous samples were acquired from each patient during surgery. High-performance liquid chromatography was used to determine the concentration of penciclovir in each sample. Exclusion criteria included prior vitrectomy, compromised blood-retina barrier, renal or hepatic disease, human immunodeficiency virus infection, bone marrow or renal transplantation, pregnancy or breastfeeding, history of adverse reaction or allergy to famciclovir or penciclovir, and antiviral, probenecid, or cimetidine use within 1 month of surgery. Results Ten eyes of 10 patients ranging in age from 26 to 82 were included. All patients had normal renal and hepatic function as determined by history and laboratory values. Mean serum penciclovir concentration ± standard deviation was 4.45 ± 1.31 μg/ml (range, 2.51 to 6.34 μg/ml). Mean vitreous penciclovir concentration was 1.21 ± 0.38 μg/ml (range, 0.39 to 1.88 μg/ml). Mean vitreous-to-serum concentration ratio of penciclovir was 0.28 ± 0.09 (range, 0.16 to 0.41). Conclusions Oral administration of famciclovir results in vitreous concentrations of penciclovir within the inhibitory ranges for herpes simplex 1, herpes simplex 2, and varicella zoster virus. Oral famciclovir may be a reasonable alternative to intravenous acyclovir (Zovirax; GlaxoSmithKline) in the treatment of acute retinal necrosis, especially in cases of acyclovir resistance or patient inability to tolerate prolonged intravenous treatment.

Purpose. The physical and chemical stability of repackaged acetylcysteine 600 mg/3 mL solution in oral syringes stored under refrigeration or at room temperature was studied for six months; a cost analysis was also conducted. Methods. Acetylcysteine 20% solution for inhalation was repackaged undiluted as 600 mg/3 mL in capped oral syringes and stored either under refrigeration or at room temperature exposed to fluorescent light. Four samples for each storage condition were analyzed in duplicate on day zero, weekly for the first month, and then every two weeks during months 2–6. Physical stability was assessed, and the chemical stability of acetylcysteine was evaluated by high-performance liquid chromatography. Results. Acetylcysteine solution in syringes was physically stable during the entire six-month study period. When stored at room temperature, acetylcysteine retained 99% of the original concentration at three months and 95% at six months after preparation of the syringes. Loss of acetylcysteine was