William J Olney’s research while affiliated with University of Kentucky and other places

Background Daptomycin is a high‐use intravenous antimicrobial agent affording the convenience of once‐daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight‐based dosing but this approach has not been studied prospectively. Methods This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non‐obese adults. At least, three daptomycin concentrations were measured at steady‐state for each patient. A population pharmacokinetic model was constructed to evaluate concentration‐time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24‐h area under the curve (AUC 0‐24 ) ≥ 666 mg∙h/L) and toxicity (minimum concentration ( C min ) ≥24.3 mg/L) targets for fixed (500–1000 mg) and weight‐based (6–12 mg/kg) daptomycin doses. Results Thirty‐one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC 0‐24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight‐based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight‐based regimens. Conclusions Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy‐to‐toxicity ratio, transitions of care, and costs compared to weight‐based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient‐specific basis.

Background: Appropriate antimicrobial therapy for the management of intra-abdominal infection (IAI) continues to evolve based on available literature. The Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial provided evidence to support four days of antibiotic agents in IAI post-source control but excluded patients with a planned re-laparotomy. This study aimed to determine the short- and long-term recurrent infection risk in this population. Patients and Methods: This is a single-center, retrospective, observational study of adult patients admitted to a quaternary medical center between January 1, 2016, and August 1, 2022, with IAI requiring planned laparotomy. Patients were designated as receiving five or less days of antibiotic agents (short course) or more than five days (long course) after source control. The primary outcome was IAI recurrence within 30 days. Results: Of the 104 patients who met inclusion criteria, 78 were included in analysis. Average age was 57 ± 13.3 years, 56% were male, 94% Caucasian, with a mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 17 ± 7.09. All other baseline characteristics and clinical severity markers were similar between the two groups. Regarding the primary outcome of IAI recurrence, there was no difference when comparing those who received short course versus those who received long course therapy (41.2% vs. 44.4%; p = 0.781). No differences were found between groups with respect to secondary outcomes. Conclusions: In patients admitted with IAI managed with planned re-laparotomy those who received short course antimicrobial therapy were not found to have an increase in IAI recurrence compared to those with longer courses of therapy.

Introduction Buprenorphine is a frequently used medication for opioid use disorder and misunderstanding buprenorphine's unique pharmacology has historically complicated perioperative analgesia. The purpose of this study was to evaluate the association of perioperative buprenorphine continuation in patients with substance use disorder on perioperative opioid use. Materials and methods This was a single-center retrospective study at a level 1 trauma academic medical center. Adult patients using outpatient buprenorphine for medication for opioid use disorder admitted with an operating room booking were included. Patients were grouped (continuation, withheld) retrospectively based upon the decision to continue or omit buprenorphine therapy while admitted. The primary outcome of the study was any use of full mu-opioid agonists during days 1-7 of admission. Secondary outcomes included length of stay and average pain scores during days 1-7 of admission. Results 43.4% of patients in the continuation cohort used no full mu-opioid agonists during days 1-7 compared to 3.1% of patients in the withheld cohort (P < 0.001). No significant difference in median length of stay was noted (4.7 d [2.8-6.6] versus 6.1 d [4.0-8.2], P = 0.36). There was no statistical difference in average pain scores on postoperative days 1 (5.2 versus 6.9, P = 0.82) and 7 (0 versus 0, P = 0.41). Conclusions Perioperative continuation of buprenorphine is associated with reduced use of alternative full mu-opioid agents while admitted without impacting pain scores.

Background Critically ill patients are at increased risk for fluid overload, but objective prediction tools to guide clinical decision-making are lacking. The MRC-ICU scoring tool is an objective tool for measuring medication regimen complexity. Objective To evaluate the relationship between MRC-ICU score and fluid overload in critically ill patients. Methods In this multi-center, retrospective, observational study, the relationship between MRC-ICU and the risk of fluid overload was examined. Patient demographics, fluid balance at day 3 of ICU admission, MRC-ICU score at 24 hours, and clinical outcomes were collected from the medical record. The primary outcome was relationship between MRC-ICU and fluid overload. To analyze this, MRC-ICU scores were divided into tertiles (low, moderate, high), and binary logistic regression was performed. Linear regression was performed to determine variables associated with positive fluid balance. Results A total of 125 patients were included. The median MRC-ICU score at 24 hours of ICU admission for low, moderate, and high tertiles were 9, 15, and 21, respectively. For each point increase in MRC-ICU, a 13% increase in the likelihood of fluid overload was observed (OR 1.128, 95% CI 1.028-1.238, p = 0.011). The MRC-ICU score was positively associated with fluid balance at day 3 (β-coefficient 218.455, 95% CI 94.693-342.217, p = 0.001) when controlling for age, gender, and SOFA score. Conclusions Medication regimen complexity demonstrated a weakly positive correlation with fluid overload in critically ill patients. Future studies are necessary to establish the MRC-ICU as a predictor to identify patients at risk of fluid overload.

Objective: To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d). Data sources: A PubMed/MEDLINE literature search was performed (January 2000 to December 2020) using the search terms daptomycin, high dose, and dosing. Review article references and society guidelines were reviewed. Study selection and data extraction: Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included. Data synthesis: Experimentally, daptomycin outperforms other antimicrobials for high inoculum and biofilm-associated infections. Clinically, high-dose daptomycin is supported as salvage and first-line therapy for endocarditis and bacteremia, primarily when caused by methicillin-resistant Staphylococcus aureus (when vancomycin minimum inhibitory concentration is >1 mg/L) and Enterococcus. High-dose daptomycin appears effective for osteomyelitis and central nervous system infections, although comparative studies are lacking. High dosing in renal replacement therapy requires considering clearance modality to achieve exposures like normal renal function. Weight-based dosing in obesity draws concern for elevated exposures, although high doses have not been evaluated kinetically in obesity. Some data show benefits of high doses in overweight populations. Burn patients clear daptomycin more rapidly, and high doses may only achieve drug exposures similar to standard doses (6 mg/kg). Relevance to patient care and clinical practice: This review analyzes the efficacy and safety of high-dose daptomycin in serious gram-positive infections. Discussion of specific infectious etiologies and patient populations should encourage clinicians to evaluate their daptomycin dosing standards. Conclusions: The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.

Background The MRC-ICU, a novel regimen complexity scoring tool, provides an objective measure of medication regimen complexity in critically ill patients. The MRC-ICU may have the ability to evaluate the impact of critical care pharmacists on patient outcomes but requires further validation. The objective of this study was to confirm the external validity of the MRC-ICU scoring tool at multiple institutions and intensive care unit (ICU) settings. Methods This was a multicenter, prospective, observational study. The electronic medical record was reviewed to collect patient demographics and patient outcomes, and the medication administration record was reviewed to collect MRC-ICU scores at 24 hours, 48 hours, and ICU discharge. Validation was performed by assessing convergent and divergent validity of the score. Spearman rank-order correlation was used to determine correlation. Results A total of 230 patients were evaluated across both centers in both medical ICUs and surgical ICUs. Differences between the original center and the new site included that total number of orders (29 vs 126; P < 0.001) and total number of medication orders (17 vs 36; P < 0.001) were higher at the new site, whereas the original site had higher overall MRC-ICU scores (14 vs 11; P = 0.004). The MRC-ICU showed appropriate convergent validity with number of orders and medication orders (all P < 0.001) and appropriate divergent validity with no significant correlation found between age, weight, or gender (all P > 0.05). Conclusions External validity of the MRC-ICU has been confirmed through evaluation at an external site and in the surgical ICU population. The MRC-ICU scoring tool requires prospective evaluation to provide objective data regarding optimal pharmacist use.

Background Clinical pharmacists are established members of the interprofessional patient care team, but limited guidance for the optimal utilization of pharmacy resources is available. Objective measurement of medication regimen complexity offers a novel process for evaluating pharmacist activity. The purpose of this study was to evaluate the relationship between medication regimen complexity, as measured by a novel medication regimen complexity scoring tool (MRC‐ICU), and both pharmacist interventions and drug‐drug interactions (DDIs). Methods This was a multi‐center, prospective, observational study. The electronic medical record was reviewed to collect patient demographics, patient outcomes, and MRC‐ICU and modified MRC‐ICU (mMRC‐ICU) score at 24, 48 hours, and at discharge. Pharmacist interventions were recorded during the patients' intensive care unit (ICU) stay. DDIs were also evaluated at 24, 48 hours, and at discharge. Spearman's rank‐order correlation was used to determine any correlation between the MRC‐ICU score at each time point and the number of pharmacist interventions and DDIs. Results A total of 153 patients were evaluated from both centers. The median MRC‐ICU at 24 hours was 11 (interquartile range [IQR] 7‐15). MRC‐ICU at 24 hours was correlated with interventions at 24 hours ( r s .439, P <.001). Furthermore, MRC‐ICU was correlated with total DDIs ( r s .4, P < .001). A modified version of the MRC‐ICU was also correlated with number of pharmacist interventions ( P < .001) and DDIs ( P < .001). Conclusions Medication regimen complexity showed a relationship with number of pharmacist interventions and number of DDIs.