Search

The HyFlex course structure allows students to attend class in-person or via synchronous videoconferencing technology. This model has been described, but no data are available in pharmacy curricula.Students enrolled in Grand Rounds (GR) were eligible. The GR Engagement Assessment Tool (GREAT) measured engagement three times during the semester. Eighteen statements across four domains were rated using a five-point Likert scale (1 = not true at all and 5 = completely true). Free-text responses were collected for qualitative analysis. The primary outcome was the difference in GR engagement between students attending in-person vs. remotely. Descriptive statistics were used for demographic information. Wilcoxon rank-sum tests compared Likert-scale responses between in-person and remote attendance.Surveys included 128 responses from 88 unique students. There were no differences between remote and in-person attendance for the boredom and elaboration domains. In-person students reported listening more intently (median 4, IQR [3,4]; P = .03). In-person students felt the material was more practical (median 4, IQR [4,5]) than remote students (median 4, IQR [3,4]; P = .002) and more applicable to other situations (median 3, IQR [3,5]) than remote students (median 3, IQR [2,4]; P = .04). Qualitative analysis of the entire cohort demonstrated five themes for satisfaction: safety, flexibility, convenience, technology, and professionalism.There were subtle differences in student engagement or satisfaction using the HyFlex model. This study supports the expansion of this methodology to similar courses where remote instruction is needed.

Background: Propofol is a key component for the management of sedation and shivering during targeted temperature management (TTM) following cardiac arrest. The cardiac depressant effects of propofol have not been described during TTM and may be especially relevant given the stress to the myocardium following cardiac arrest. The purpose of this study is to describe hemodynamic changes associated with propofol administration during TTM. Methods: This single center, retrospective cohort study evaluated adult patients who received a propofol infusion for at least 30 minutes during TTM. The primary outcome was the change in cardiovascular Sequential Organ Failure Assessment (cvSOFA) score 30 minutes after propofol initiation. Secondary outcomes included change in systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate (HR), and vasopressor requirements (VR) expressed as norepinephrine equivalents at 30, 60, 120, 180, and 240 minutes after propofol initiation. A multivariate regression was performed to assess the influence of propofol and body temperature on MAP, while controlling for vasopressor dose and cardiac arrest hospital prognosis (CAHP) score. Results: The cohort included 40 patients with a median CAHP score of 197. The goal temperature of 33°C was achieved for all patients. The median cvSOFA score was 1 at baseline and 0.5 at 30 minutes, with a non-significant change after propofol initiation ( P = .96). SBP and MAP reductions were the greatest at 60 minutes (17 and 8 mmHg; P

Persons with obesity (PwO) represent approximately 50% of acute bacterial skin and skin structure infections (ABSSSIs) in the United States (US). There are currently insufficient data in PwO for drugs used for ABSSSIs. We conducted a scoping review of randomized controlled trials (RCTs) published between 2000 and 2022 to describe how frequently body size measures were reported. Weight and/or body mass index (BMI) were recorded in approximately 50% of the 69 RCTs. The average weights or BMIs were lower than US averages for most RCTs reporting data. None evaluated the impact of body size on outcomes in the original publication. Only 30% of newly approved drugs mention PwO representation in the prescribing information. More representative recruitment of PwO into RCTs is needed to help clinicians evaluate efficacy in these patients. We suggest that the Food and Drug Administration require companies to submit plans to ensure adequate PwO inclusion and that authors of RCTs report subgroup results based on body size.

Background: : Proton pump inhibitors (PPI) are associated with Clostridium difficile infection (CDI). Impact of the route of administration is unknown.Research Design and Methods: Patients in Multiparameter Intelligent Monitoring in Intensive Care II database (MIMIC-II) from 2001 to 2008, >18 years old, admitted to medical, surgical, or cardiac ICUs were included. PPI exposures were omeprazole, esomeprazole, lansoprazole, and pantoprazole. PPI administration routes were oral or intravenous. Patients who received histamine receptor antagonists (H2RA) were the control arm. CDI was identified using ICD-9 diagnostic code 008.45. Multiple logistic regression analysis was performed to calculate odds ratios (OR).Results: The study included 16,820 patients (57% male) with a mean age of 63 (SD±17) years and hospitalization duration of 10.2 days (SD±11). Pantoprazole was the most common PPI (94%). CDI occurred in 2.4% and more in patients receiving PPIs than H2RAs (3.0% vs. 0.8%, p < 0.001). CDI prevalence increased with intravenous (95%CI = 1.69-3.39, OR 2.4) and oral (95%CI = 1.59-3.27, OR 2.3) PPI use compared to H2RAs. CDI prevalence was not associated with PPI route in the multivariable model (OR 1.07, 95%CI 0.86-1.34).Conclusions: Both intravenous and oral PPI use in the ICU were independently associated with CDI.

PURPOSE This study aimed to investigate the role of regional f0 inhomogeneity in spiral hyperpolarized 13 C image quality and to develop measures to alleviate these effects. METHODS Field map correction of hyperpolarized 13 C cardiac imaging using spiral readouts was evaluated in healthy subjects. Spiral readouts with differing duration (26 and 45 ms) but similar resolution were compared with respect to off-resonance performance and image quality. An f0 map-based image correction based on the multifrequency interpolation (MFI) method was implemented and compared to correction using a global frequency shift alone. Estimation of an unknown frequency shift was performed by maximizing a sharpness objective based on the Sobel variance. The apparent full width half at maximum (FWHM) of the myocardial wall on [13 C]bicarbonate was used to estimate blur. RESULTS Mean myocardial wall FWHM measurements were unchanged with the short readout pre-correction (14.1 ± 2.9 mm) and post-MFI correction (14.1 ± 3.4 mm), but significantly decreased in the long waveform (20.6 ± 6.6 mm uncorrected, 17.7 ± 7.0 corrected, P = .007). Bicarbonate signal-to-noise ratio (SNR) of the images acquired with the long waveform were increased by 1.4 ± 0.3 compared to those acquired with the short waveform (predicted 1.32). Improvement of image quality was observed for all metabolites with f0 correction. CONCLUSIONS f0 -map correction reduced blur and recovered signal from dropouts, particularly along the posterior myocardial wall. The low image SNR of [13 C]bicarbonate can be compensated with longer duration readouts but at the expense of increased f0 artifacts, which can be partially corrected for with the proposed methods.

(1) Background: Fidaxomicin has been shown to significantly reduce

No consensus exists regarding optimal dosing of norepinephrine in septic shock. We aimed to evaluate if weight-based dosing (WBD) lead to higher norepinephrine doses when achieving goal mean arterial pressure (MAP) than non-weight-based dosing (non-WBD). This was a retrospective cohort study conducted after standardization of norepinephrine dosing within a cardiopulmonary ICU. Patients received non-WBD prior to standardization (November 2018–October 2019) and WBD afterwards (November 2019–October 2020). The primary outcome was the norepinephrine dose needed to attain goal MAP. Secondary outcomes included time to goal MAP, duration of norepinephrine therapy, duration of mechanical ventilation, and treatment-related adverse effects. A total of 189 patients were included (WBD 97; non-WBD 92). There was a significantly lower norepinephrine dose at goal MAP (WBD 0.05, IQR 0.02, 0.07; non-WBD 0.07, IQR 0.05, 0.14; p < 0.005) and initial norepinephrine dose (WBD 0.02, IQR 0.01, 0.05; non-WBD 0.06, 0.04, 0.12; p < 0.005) in the WBD group. No difference was observed in achievement of goal MAP (WBD 73%; non-WBD 78%; p = 0.09) or time until goal MAP (WBD 18, IQR 0, 60; non-WBD 30, IQR 14, 60; p = 0.84). WBD may lead to lower norepinephrine doses. Both strategies achieved goal MAP with no significant difference in time to goal.

(1) Background: Excessive intravenous therapy (EIV) is associated with negative consequences, but guidelines are unclear about when switching to oral therapy is appropriate. (2) Methods: This cohort included patients aged ≥18 years receiving ≥48 h of antimicrobial therapy for bacteremia due to Escherichia coli, Pseudomonas aeruginosa, Enterobacter, Klebsiella, Acinetobacter, or Stenotrophomonas maltophilia from 1/01/2008–8/31/2011. Patients with a polymicrobial infection or recurrent bacteremia were excluded. Potential EIV (PEIV) was defined as days of intravenous antibiotic therapy beyond having a normal WBC count for 24 h and being afebrile for 48 h until discharge or death. (3) Results: Sixty-nine percent of patients had PEIV. Patients who received PEIV were more likely to receive intravenous therapy until discharge (46 vs. 16%, p < 0.001). Receipt of PEIV was associated with a longer mean time to receiving oral antimicrobials (8.7 vs. 3 days, p < 0.001). The only factors that impacted EIV days in the multivariable linear regression model were the source of infection (urinary tract) (coefficient −1.54, 95%CI −2.82 to −0.26) and Pitt bacteremia score (coefficient 0.51, 95%CI 0.10 to 0.92). (4) Conclusions: PEIV is common in inpatients with Gram-negative bacteremia. Clinicians should look to avoid PEIV in the inpatient setting.

Piperacillin/tazobactam (TZP) has been associated with nephrotoxicity in patients receiving vancomycin. Its impact on nephrotoxicity in patients with Gram-negative bacteraemia (GNB) is unclear. This study evaluated the impact of TZP on nephrotoxicity in patients with GNB. This retrospective cohort included patients aged ≥18 years receiving ≥48 h of therapy for bacteraemia due to Escherichia coli, Pseudomonas aeruginosa, Enterobacter, Klebsiella, Acinetobacter or Stenotrophomonas maltophilia from 1/01/2008–8/31/2011. Patients with baseline serum creatinine (SCr) ≥3.5 mg/dL, polymicrobial infection or recurrent bacteraemia were excluded. Nephrotoxicity was defined as a ≥0.5 mg/dL increase in SCr or ≥50% increase from baseline for ≥2 consecutive days. Any variable demonstrating a 10% change in exposure effect was retained in the final model. All variables biologically reasonable causes of nephrotoxicity were also considered for inclusion. The median age of the cohort (n = 292) was 76 years; 38.0% had a cancer diagnosis and ICU residence was common (21.9%). There was no difference in nephrotoxicity incidence based on days of TZP received (0 days, 13.6%; 1–2 days, 14.7%; 3–4 days, 6.9%; ≥5 days, 16.7%; P = 0.71). In multivariable analysis, baseline SCr, total body weight and vasopressor use were independently associated with nephrotoxicity. Duration of TZP was not associated with nephrotoxicity in multivariable analysis (1–2 days, OR = 0.91, 95% CI 0.39–2.12; 3–4 days, OR = 0.48, 95% CI 0.10–2.46; ≥5 days, OR = 0.57, 95% CI 0.11–3.02). In this cohort of GNB patients, duration of TZP was not associated with nephrotoxicity.

Background Glioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.13C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors. Methods Three patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1–2 days prior to tumor resection using a 13C/1H dual-frequency RF coil and a 13C/1H-integrated MR protocol, which consists of a series of 1H MR sequences (T2 FLAIR, arterial spin labeling and contrast-enhanced [CE] T1) and 13C spectroscopic imaging with hyperpolarized [1-13C]pyruvate. Dynamic spiral chemical shift imaging was used for 13C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the 13C spectroscopic images. Results Each tumor was histologically confirmed to be a WHO grade IV glioblastoma with isocitrate dehydrogenase wild type. Total hyperpolarized 13C signals detected near the tumor mass reflected altered tissue perfusion near the tumor. For each tumor, a hyperintense [1-13C]lactate signal was detected both within CE and T2-FLAIR regions on the 1H diagnostic images (P = .008). [13C]bicarbonate signal was maintained or decreased in the lesion but the observation was not significant (P = .3). Conclusions Prior to surgical resection, 13C MR spectroscopic imaging with hyperpolarized pyruvate reveals increased lactate production in regions of histologically confirmed glioblastoma.

Introduction Obtaining a residency has become more competitive as more pharmacy students seek postgraduate training. This is likely due to pharmacist positions increasing in clinical settings. To be fully prepared, students seeking residency positions should be trained for the interview process by their pharmacy school. Methods Mock residency interviews (MRI) were conducted at the Texas Tech University Health Sciences Center School of Pharmacy which included components of typical residency interviews. The primary outcome compared residency match rates for MRI participants vs. non-participants. Secondary outcomes evaluated student preparedness, student and faculty feedback, and satisfaction/benefit of the event along with comparison of school vs. national match rate and assessment of those matching compared to grade point average (GPA). Results Match rates were similar between MRI participants vs. non-participants (75% vs. 73%) with significant difference in Phase I match rates between MRI participants vs. non-participants (75% vs. 51%, P = .007). MRI was significantly associated with Phase I matching in the multivariable analysis (odds ratio (OR) = 2.81, 95% CI 1.27–6.22). The overall school's match rate exceeded the national two out of three years in the quality improvement project period. GPA was the only other factor independently associated with Phase I matching (OR = 1.15, 95% CI 1.01–1.32). Students and faculty consistently reported positive feedback following participation. Conclusions MRI are valuable and are making a difference as indicated by improved Phase I match rates for those that participated. Students and faculty reported an increase in preparedness and overall satisfaction after attending MRI.

The impact of total body weight (TBW) on the development of acute kidney injury (AKI) associated with gram-negative bacteremia has not been previously evaluated.The cohort included 323 patients/ = 18 years old with gram-negative bacteremia (1/1/2008-8/31/2011) who received/ = 48 hours of antibiotics. We compared the incidence of AKI in patients with a TBW/ = 80kg vs.80kg with a multivariable stepwise logistic regression adjusting for age/ = 70 years, baseline serum creatinine of2.0 mg/dl, and receipt of a vasopressor. AKI was defined as an increase of 0.5 mg/dL or a 50% increase from baseline for at least two consecutive days.The cohort was 62% TBW/ = 80kg and 38% TBW80kg. TBW80kg patients had higher risk of AKI (24% vs. 9%, p 0.001), which was significant in the multivariable analysis (OR 3.41, 95% CI 1.73-6.73). A baseline serum creatinine of2.0 mg/dl and vasopressor use were also independently associated with AKI.TBW80kg was associated with the development of AKI. However, the mechanism for this association is not clear.

Background: Pharmacologic thromboprophylaxis (PTP) is the mainstay prevention strategy for venous thromboembolism (VTE). PTP agents traditionally dosed, like unfractionated heparin (UFH) and enoxaparin (ENOX), are associated with failure and bleeding in obese and underweight patients, respectively. Objectives: This study aimed to describe the prevalence of unadjusted ENOX and UFH dosing for PTP based on anthropometric measures. Patients/Methods: This was a post-hoc, multicenter, cross–sectional analysis of critically ill adults receiving PTP with ENOX or UFH. The primary outcome was the prevalence of unadjusted PTP based on body mass index (BMI) and total body weight (TBW). Definitions for dose adjustments were developed based on existing literature. A secondary outcome was to identify factors associated with unadjusted dosing per BMI and TBW using multivariable generalized linear mixed-effect models. Results: The nested cohort included 172 patients (ENOX=46, UFH=126). Unadjusted PTP was observed in 118 patients (68.6%) based on BMI and 74 (43%) per TBW. When comparing UFH to ENOX, more patients who received UFH had doses unadjusted by BMI (78.6% vs. 41.3%, p100kg (OR 4.85, 95% CI 2.15-10.96) were independently associated with unadjusted PTP based on TBW. Conclusions: Unadjusted dosing of PTP occurs frequently in critically ill adults receiving ENOX or UFH. This was seen in body size extremes by both BMI and TBW.

The human species is becoming increasingly obese. Dapsone, which is extensively used across the globe for dermatological disorders, arachnid bites, and for treatment of several bacterial, fungal and parasitic diseases, could be affected by obesity. We performed a clinical experiment, using optimal design, in volunteers weighing 44-150 kilograms, to identify the effect of obesity on dapsone pharmacokinetic parameters based on maximum-likelihood solution via the expectation-maximization algorithm. Artificial intelligence-based multivariate adaptive regression splines were used for covariate selection, and identified weight and/or age as predictors of absorption, systemic clearance and volume of distribution. These relationships occurred only between certain patient weight and age ranges, delimited by multiple hinges and regions of discontinuity, not identified by standard pharmacometric approaches. Older and obese people have lower drug concentrations after standard dosing, but with complex patterns. Given that efficacy is concentration-dependent, optimal dapsone doses need to be personalized for obese patients. This article is protected by copyright. All rights reserved.

The impact of total body weight (TBW) on 30-day mortality associated with gram-negative bacteremia has not been previously evaluated.The cohort included 323 patients/ = 18 years old with gram-negative bacteremia (1/1/2008-8/31/2011) who received/ = 48 hours of antibiotics. We compared 30-day mortality of TBW70 kg vs./ = 70 kg with a multivariable stepwise logistic regression adjusting for age/ = 70 years, cancer diagnosis, and Pitt bacteremia score of/ = 4.The cohort was 57% TBW/ = 70 kg and 43% TBW70 kg. TBW/ = 70 kg patients had lower 30-day mortality (11.0% vs. 16.3%), which was significant in the multivariable analysis (OR 0.45, 95% CI 0.21-0.97). Cancer and Pitt bacteremia score/ = 4 were also independently associated with 30-day mortality. TBW was no longer significant when TBW50 kg patients were excluded.TBW/ = 70 kg was associated with an improved 30-day mortality; however, the high mortality rates for patients with a TBW50 kg is responsible for this association.

Purpose Results of a study to determine whether obesity is associated with acute kidney injury (AKI) among patients receiving combination therapy with piperacillin–tazobactam and vancomycin are reported. Methods A retrospective, single-center cohort study of patients who received combination therapy for at least 48 hours was conducted using data from the University of Kentucky Center for Clinical and Translational Science’s Enterprise Data Trust. Patients with chronic kidney disease, baseline creatinine clearance of less than 30 mL/min, cystic fibrosis, or missing height or weight information were excluded. Results A total of 8,125 patients were included in the cohort. Among the variables evaluated, total body weight of 91 kg or more was the variable most predictive of AKI. Patients with a weight of 91 kg or higher were more likely than lower-weight patients to have diabetes (39% versus 21%, p < 0.00001), hypertension (64% versus 47%, p < 0.00001), and heart failure (15% versus 13%, p = 0.007). The median daily vancomcyin dose was lower in patients with a weight of less than 91 kg (2,000 mg versus 3,000 mg, p < 0.00001); however, weight-based doses were lower in patients weighing 91 kg or more (25.5 mg/kg/day versus 27.9 mg/kg/day, p < 0.00001). AKI was more common in patients weighing 91 kg or more (24% versus 18%, p < 0.00001; adjusted odds ratio, 1.46 [95% confidence interval, 1.28–1.66]). Conclusion Increased total body weight increased the rate of AKI among patients concurrently treated with piperacillin–tazobactam and vancomycin independent of clinically important confounders, with an important breakpoint occurring at 91 kg.

Introduction Neuropsychiatric disorders affect millions of older adults. Despite this, there are relatively few older adults included in clinical trials evaluating treatments for psychiatric disorders. Citalopram has been evaluated in older adults with neuropsychiatric disorders and has largely been found beneficial, making the 2011 US Food and Drug Administration (FDA) safety advisory on citalopram extremely impactful. Methods A literature search was completed using the PubMed database. Results were limited to clinical trials conducted in older adults that were published in English. Results Review of the literature confirms the efficacy of citalopram in depression, anxiety, depression associated with Parkinson disease, and behavioral and psychological symptoms of dementia. Additionally, no adverse cardiac outcomes have been described related to citalopram. Discussion The FDA's evidence for applying this safety advisory to citalopram is minimal and largely based on surrogate markers, such as the QTc interval rather than clinical and safety outcomes. Citalopram is known to increase the QTc, but this increase has not been linked to adverse cardiac outcomes. The evidence for efficacy and against adverse outcomes suggests that a reevaluation of the dosing restrictions in older adults with neuropsychiatric disorders is needed.

Vancomycin-associated acute kidney injury (AKI) is a popular topic in the medical literature with few clear answers. While many studies evaluate the risk of AKI associated with vancomycin, few data are high quality and/or long in duration of follow-up. This review takes the clinician through an approach to evaluate a patient for risk of AKI. This evaluation should include patient assessment, antibiotic prescription, duration, and monitoring. Patient assessment involves evaluating severity of illness, baseline renal function, hypotension/vasopressor use, and concomitant nephrotoxins. Evaluation of antibiotic prescription includes evaluating the need for methicillin-resistant Staphylococcus aureus (MRSA) coverage and/or vancomycin use. Duration of therapy has been shown to increase the risk of AKI. Efforts to de-escalate vancomycin from the antimicrobial regimen, including MRSA nasal swabs and rapid diagnostics, should be used to lessen the likelihood of AKI. Adequate monitoring includes therapeutic drug monitoring, ongoing fluid status evaluations, and a continual reassessment of AKI risk. The issues with serum creatinine make the timely evaluation of renal function and diagnosis of the cause of AKI problematic. Most notably, concomitant piperacillin-tazobactam can increase serum creatinine via tubular secretion, resulting in higher rates of AKI being reported. The few studies evaluating the long-term prognosis of AKI in patients receiving vancomycin have found that few patients require renal replacement therapy and that the long-term risk of death is unaffected for patients surviving after the initial 28-day period.

Trimethoprim‐sulfamethoxazole (TMP‐SMX) is one of the most widely drugs on earth. The World Health Organization recommends it as an essential basic drug for all healthcare systems. Dosing is inconsistently based on weight, assuming linear relationships. Given that obesity is now a global “pandemic” it is vital that we evaluate the effect of obesity on trimethoprim‐sulfamethoxazole concentrations. We conducted a prospective clinical experiment based on optimized design strategies and artificial intelligence algorithms and found that weight and body mass index (BMI) had a profound effect on drug clearance and volume of distribution, and followed nonlinear fractal geometry‐based relationships. The findings were confirmed by demonstrating decreased TMP‐SMX peak and area under the concentration‐time curves in overweight patients based on standard regression statistics. The nonlinear relationships can now be used to identify new TMP‐SMX doses in overweight and obese patients for each of the infections caused by the >60 pathogens for which the drug is indicated.

Background The incidence of outpatient visits for skin and soft tissue infections (SSTIs) has substantially increased over the last decade. The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has made the management of S. aureus SSTIs complex and challenging. The objective of this study was to identify risk factors contributing to treatment failures associated with community-associated S. aureus skin and soft tissue infections SSTIs. Methods This was a prospective, observational study among 14 primary care clinics within the South Texas Ambulatory Research Network. The primary outcome was treatment failure within 90 days of the initial visit. Univariate associations between the explanatory variables and treatment failure were examined. A generalized linear mixed-effect model was developed to identify independent risk factors associated with treatment failure. Results Overall, 21% (22/106) patients with S. aureus SSTIs experienced treatment failure. The occurrence of treatment failure was similar among patients with methicillin-resistant S. aureus and those with methicillin-susceptible S. aureus SSTIs (19 vs. 24%; p = 0.70). Independent predictors of treatment failure among cases with S. aureus SSTIs was a duration of infection of ≥7 days prior to initial visit [aOR, 6.02 (95% CI 1.74–19.61)] and a lesion diameter size ≥5 cm [5.25 (1.58–17.20)]. Conclusions Predictors for treatment failure included a duration of infection for ≥7 days prior to the initial visit and a wound diameter of ≥5 cm. A heightened awareness of these risk factors could help direct targeted interventions in high-risk populations.

Summary Traumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of 13C-labeled substrates provides a unique opportunity to map the metabolic changes in the brain after traumatic injury in real-time without invasive procedures. In this report, we investigated two patients with acute mild TBI (Glasgow coma scale 15) but no anatomical brain injury or hemorrhage. Patients were imaged with hyperpolarized [1-13C]pyruvate MRSI 1 or 6 days after head trauma. Both patients showed significantly reduced bicarbonate (HCO3–) production, and one showed hyperintense lactate production at the injured sites. This study reports the feasibility of imaging altered metabolism using hyperpolarized pyruvate in patients with TBI, demonstrating the translatability and sensitivity of the technology to cerebral metabolic changes after mild TBI.

The purpose of this work was to develop and validate a single sensitive, selective and rapid bioanalytical method to determine ceftolozane and tazobactam concentrations in human plasma and urine and to use this method to analyze samples from a human clinical study. Human plasma and urine samples were prepared by protein precipitation using a solution of acetonitrile, water and formic acid. Following protein precipitation, samples were analyzed by liquid chromatography tandem mass spectrometry. Chromatographic resolution was achieved on a Kinetex PFP column using a gradient elution, a flow rate of 0.4 mL/min, and a total run time of 5 min. Positive electrospray ionization was employed and analytes were quantitated using multi-reaction monitoring mode. Method validation was conducted in accordance with Unites States Food and Drug Administration’s regulatory guidelines for bioanalytical method validation. Calibration curves were determined to linear over the range of 0.1 to 40 µg/mL for ceftolozane and 0.05 to 20 µg/mL for tazobactam. The method was determined to be accurate (−6.24 to 12.53 percent relative error), precise (less than 13.28 percent standard deviation) and sensitive in both human plasma and urine. Ceftolozane and tazobactam were determined to be stable across a battery of stability studies including autosampler, benchtop, freeze/thaw and long-term stability. This validated method successfully applied to human clinical samples to determine the concentration versus time profiles of the intravenously administered combination of Zerbaxa (ceftolozane-tazobactam) in burn patients.

Community-acquired pneumonia is the sixth leading cause of death in the USA. Adherence to the 2007 Infectious Diseases Society of America/American Thoracic Society community-acquired pneumonia guidelines has been associated with improved clinical outcomes. However, choice between guideline-recommended treatments is at the discretion of the prescribing clinician. This review is intended to discuss the characteristics of these treatment options including dosing frequency, dose adjustment for renal/hepatic dysfunction, serious/common adverse events, drug interactions, lung penetration, pharmacokinetic-pharmacodynamic target and effect of obesity to help guide antimicrobial selection. An increasing portion of patients are receiving expanded empiric coverage for methicillin-resistant Staphylococcus aureus as recommended by the American Thoracic Society and Infectious Diseases Society of America for healthcare-associated pneumonia. However, this expanded coverage may not be achieving the desired improvements in clinical outcomes. We expect this increasingly diverse spectrum of patients with pneumonia to eventually result in the merger of these two guidelines to include all patients with pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen in both outpatient and inpatient settings. Research to optimize the dosing of these agents is needed to slow the development of antimicrobial resistance and to decrease the likelihood of clinical failure. Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 - Present) search was performed to identify relevant literature for this review. Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones. Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections.

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a predominant pathogen resulting in significant morbidity and mortality. Optimal dosing of anti-MRSA agents is needed to help prevent the development of antimicrobial resistance and to increase the likelihood of a favorable clinical outcome.Areas covered: This review summarizes the available data for antimicrobials routinely used for MRSA infections that are not administered orally or topically. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.Expert commentary: Improvements in MIC determination and therapeutic drug monitoring are needed to fully implement individualized dosing that optimizes antimicrobial pharmacodynamics.Additional data will become available for these agents in regards to effectiveness for severe MRSA infections and pharmacokinetic data for special patient populations.

To examine the available trials evaluating the effect of obesity on the pharmacokinetic parameters of chemotherapy agents.A PubMed search (January 1977-June 2013) was conducted for English-language articles evaluating obesity and its relationship to pharmacokinetic parameters of chemotherapy agents. Search terms included: chemotherapy, obesity, excess weight, overweight, neoplasm, pharmacokinetics, dosing, cancer, body mass index, toxicity, efficacy, body surface area.All articles were critically evaluated, and all pertinent information was included. Studies were included if they addressed obesity and pharmacokinetic parameters.Obesity and cancer are preeminent health care challenges in the 21st century, with obese persons being at an increased risk of cancer. Given this background, it is troubling that limited information is available for dosing chemotherapy agents in obese patients. Pharmacokinetic parameters of other drug classes have been affected by increased weight. It is important to evaluate the effect on chemotherapy agents given their narrow therapeutic window. Dose capping has been used to limit excess toxicity in obese patients at the risk of providing a less-effective regimen. Data suggest an increased dose of carboplatin, cisplatin, ifosfamide, paclitaxel, and vincristine may be needed in obese patients. The literature also suggests that no dosing alteration may be necessary for obese patients receiving topoisomerase I and II inhibitors, 5-fluorouracil, methotrexate, and docetaxel. A dose decrease might be suitable for cyclophosphamide.Some cytotoxic agents used in practice have altered pharmacokinetics in obese patients. Studies prospectively validating dose individualization for obese patients are needed.

Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergilllosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6) 3/4 . The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6) 3/2 , an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a “floating” instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.)

SUMMARYSkin and soft tissue infections (SSTIs) due to Staphylococcus aureus have become increasingly common in the outpatient setting; however, risk factors for differentiating methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) SSTIs are needed to better inform antibiotic treatment decisions. We performed a case-case-control study within 14 primary-care clinics in South Texas from 2007 to 2015. Overall, 325 patients [S. aureus SSTI cases (case group 1, n = 175); MRSA SSTI cases (case group 2, n = 115); MSSA SSTI cases (case group 3, n = 60); uninfected control group (control, n = 150)] were evaluated. Each case group was compared to the control group, and then qualitatively contrasted to identify unique risk factors associated with S. aureus, MRSA, and MSSA SSTIs. Overall, prior SSTIs [adjusted odds ratio (aOR) 7·60, 95% confidence interval (CI) 3·31–17·45], male gender (aOR 1·74, 95% CI 1·06–2·85), and absence of healthcare occupation status (aOR 0·14, 95% CI 0·03–0·68) were independently associated with S. aureus SSTIs. The only unique risk factor for community-associated (CA)-MRSA SSTIs was a high body weight (⩾110 kg) (aOR 2·03, 95% CI 1·01–4·09).

We conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of 40 kg/m 2 , who received a single oral dose of 1,600 mg ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6) 3/4 and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized ethambutol dosing regimens need to be designed for obese and extremely obese patients.

The majority of Americans are overweight, and the incidence of obesity continues to increase. This trend predisposes people to a number of deleterious consequences, including the metabolic syndrome and other conditions that lead to a greater number of hospital admissions. Invasive candidiasis is an important nosocomial infection that results from these admissions. Echinocandins such as micafungin are indicated for treatment. We have previously demonstrated that overweight patients exhibit higher micafungin systemic clearance (SCL) than leaner patients. We hypothesized that obese and extremely obese people would show even higher SCL than merely overweight patients. To test this, we performed a prospective study of 36 adult volunteers randomized to receive a single dose of either 100 mg or 300 mg of micafungin whose body mass index fell within one of the following categories: 40 kg/m 2 . The male-to-female ratio was 1:1. The minimum weight was 43 kg, the median 97 kg, and the maximum weight 155 kg. A two-compartment model was examined using the maximum likelihood solution via the expectation-maximization algorithm. Men had a higher median SCL of 1.53 liters/h versus 1.29 liters/h ( P = 0.01) in the Mann-Whitney U-test. The typical SCL was 1.04 liters/h but increased by a factor of (weight/66) 0.75 as weight increased above 66 kg. Thus, the relationship between micafungin SCL and weight in adults is best described by fractal-geometry-based laws. Furthermore, micafungin SCL continues to increase as weight increases, with no obvious plateau. This leads to a requirement for strategies to determine individualized dosing levels for obese and extremely obese patients.

Purpose: Clinicians typically cap an obese patient’s chemotherapy regimen as a result of concern for excessive toxicity, without adequate clinical evidence. The purpose of this study was to evaluate the incidence of grade 3 or 4 myelosuppression in obese patients versus nonobese patients with capped dosing on the basis of body surface area (BSA). Methods: A retrospective chart review was conducted comparing obese patients (body mass index [BMI] 30 kg/m 2 ) with capped dosing who received capped chemotherapy doses at a BSA of 2.2 m 2 with nonobese (BMI 25 kg/m 2 ) patients with lung, colorectal, or hormone-refractory prostate cancer. Results: Forty-one obese patients with capped dosing and 244 nonobese patients were included. The obese patient group received on average significantly more cycles of chemotherapy (6 v 4 cycles) compared with the nonobese group. The overall incidence of any chemotherapy-related toxicity was 34% in the obese patient group, compared with 42% in the nonobese patient group (P .356). The incidence of grade 3 or 4 myelosuppression was lower, but not statistically significant, in obese patients with capped dosing compared with the nonobese patient group (22% v 27%; P .493). Conclusions: Overall, obese patients with capped dosing experienced a lower incidence of severe myelosuppression and tolerated more cycles of chemotherapy compared with nonobese patients. The better tolerability of chemotherapy in obese patients with capped dosing suggests that there is room to increase the dose in obese patients above the nationally recognized BSA cap of 2.0 m 2 , especially in early-stage lung or colon cancers in which the intention of treatment is curative.

Nosocomial pneumonia is a major cause of morbidity and mortality for hospitalized patients. Antimicrobial resistance is increasing, creating a strain between ensuring the provision of adequate empiric therapy and slowing the development of antimicrobial resistance. Excessive antimicrobial therapy places patients are at greater risk of drug interactions, adverse events, and superinfections. Ways to maximize adequate empiric therapy include (1) categorizing each patient’s risk of being infected with a multidrug-resistant pathogen and knowledge of local susceptibility patterns, (2) de-escalating antimicrobial therapy to decrease the rates of superinfections such as Clostridium difficile, and (3) limiting the duration of therapy to decrease the likelihood of adverse events, drug interactions, and antimicrobial resistance. Pharmacodynamically enhanced dosing regimens also have the potential to improve clinical outcomes and slow the development of antimicrobial resistance. Drugs whose killing is optimized by the percentage time above the minimum inhibitory concentration (MIC), such as β-lactams, can be given by continuous or extended infusion to provide superior pharmacodynamic (PD) target attainment rates compared with traditional regimens. Drugs whose killing is optimized with a high-peak plasma concentration to MIC ratio (eg, aminoglycosides) should be administered once daily to maximize the likelihood of achieve optimal target attainment rates. Drugs whose killing is optimized by the ratio of the area under the curve (AUC) to MIC ratio (eg, fluoroquinolones) depend on the total daily dose as opposed to the dosing schedule or infusion time. Determining the optimal drug dosing schedules for obese patients remains critical because these patients have may have significantly increased volumes of distribution and clearance rates compared to normal weight patients. Optimizing the use of current antimicrobials is paramount to ensure quality treatment options are available, given the lack of gram-negative antimicrobials in the pipeline.