Unexpected Vancomycin Pharmacokinetic Profile Secondary to Macromolecular Complexing: A Case Series.

BACKGROUND: The optimal dosing and monitoring of vancomycin has been largely debated for decades, with key guideline changes for recommended monitoring in 2009 and 2020. Current and past practices for pharmacokinetic dose optimization use serum drug assays to guide dose adjustment to effectively balance efficacy and the risks of toxicity. These assays detect both bound and unbound serum concentrations. Vancomycin is believed to be 50%-55% protein bound in most cases; however, some variability in this parameter has been previously published. The authors report 2 cases of abnormal vancomycin pharmacokinetics discovered based on unexpected serum levels during routine clinical care. METHODS: Unexpected vancomycin levels, observed during clinical care for 2 separate patients, were further evaluated to determine the source of the abnormal pharmacokinetics. In case 1, serial dilution was performed to assure that assay interference was not associated with the significant elevation (>100 mg/L). In both cases, samples were filtered using a Millipore Centrifree 30 KDa centrifugal filter to separate bound vancomycin, with a Protein G spin kit used to bind IgG and remove IgG complexes from the patient sample. In case 2, a polyethylene glycol precipitation was also performed to precipitate large-molecular-weight complexes. RESULTS: In both cases, laboratory analysis revealed abnormal vancomycin protein-binding profiles with macromolecular complex formation. Immunoglobulin G played a role in the macrocomplex in both patients. CONCLUSIONS: In cases of unusual or unexpected vancomycin pharmacokinetics in the absence of renal dysfunction, an abnormal protein-binding profile should be considered. Bound vancomycin may yield elevated serum levels, leading to poorly informed dose adjustments and risk for treatment failure. Given implications for therapeutic drug monitoring and unknown impacts on efficacy and toxicity, further investigations into population incidence and risk factors for abnormal protein binding of vancomycin are warranted.

Development and validation of a model to predict acute kidney injury following high-dose methotrexate in patients with lymphoma.

STUDY OBJECTIVE: To develop and validate a model for predicting acute kidney injury (AKI) after high-dose methotrexate (HDMTX) exposure. DESIGN: Retrospective analysis. SETTING: Multisite integrated health system throughout Minnesota and Wisconsin. PATIENTS: Adult patients with lymphoma who received HDMTX as a 4-h infusion. MEASUREMENTS AND MAIN RESULTS: LASSO methodology was used to identify factors available at the outset of therapy that predicted incident AKI within 7 days following HDMTX. The model was then validated in an independent cohort. The incidence of AKI within 7 days following HDMTX was 21.6% (95% confidence interval (CI) 18.4%-24.8%) in the derivation cohort (435 unique patients who received a total of 1642 doses of HDMTX) and 15.6% (95% CI 5.3%-24.8%) in the validation cohort (55 unique patients who received a total of 247 doses of HDMTX). Factors significantly associated with AKI after HDMTX in the multivariable model included age ≥ 55 years, male sex, and lower HDMTX dose number. Other factors that were not found to be significantly associated with AKI on multivariable analysis, but were included in the final model, were body surface area, Charlson Comorbidity Index, and estimated glomerular filtration rate. The c-statistic of the model was 0.72 (95% CI 0.69-0.75) in the derivation cohort and 0.72 (95% CI 0.60-0.84) in the validation cohort. CONCLUSION: This model utilizing identified sociodemographic and clinical factors is predictive of AKI following HDMTX administration in adult patients with lymphoma.

Assessment of gender differences in letters of recommendation for pharmacy residency applicants.

PURPOSE: Letters of recommendation (LORs) are highly regarded components of pharmacy residency applications, as they provide insight into an applicant's character and capabilities. In other medical fields, differences in language have been reported for letters written for female and male applicants; however, data on gender differences in LORs for pharmacy residency applications are currently lacking. METHODS: LORs for applicants to our institution's postgraduate year 1 pharmacy residency program for the 2019-2020 academic year were extracted and processed by a natural language processing service. Words within 18 categories were identified and counted for each LOR. Total word count was also compared. RESULTS: Of the 473 LORs included for analysis, 320 (67.7%) were written for female applicants and 153 (32.3%) were written for male applicants. Approximately two-thirds of all writers were women for both female and male applicants. In comparing letters for women and men, there was a statistically significant difference in the percentage of LORs that contained terms in categories described as gendered, solitary/reserved, and desire. There was no statistically significant difference in total word count or in the presence of words in other categories such as grindstone, standout, agentic, or communal. When controlling for grade point average, writer gender, duration that the writer knew the applicant, and the writer's professional position, there were no changes to the statistical findings. CONCLUSION: Letters written for female and male applicants were largely similar with regard to length and word categories utilized. While no clear gender bias was found when evaluating pharmacy residency LORs, writers must continue to assess their implicit biases and how those biases might affect a candidate's application.

Incidence of Pneumocystis jirovecii pneumonia utilizing a polymerase chain reaction-based diagnosis in patients receiving bendamustine.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening infection occurring in patients receiving bendamustine. The poorly defined incidence, particularly when utilizing polymerase chain reaction (PCR)-based diagnostic techniques, precipitates unclear prophylaxis recommendations. Our objective was to determine the cumulative incidence of PJP diagnosed by single copy target, non-nested PCR in patients receiving bendamustine. METHODS: Patients were evaluated for PJP from initiation of bendamustine through 9 months after the last administration. The cumulative incidence of PJP was estimated using the Aalen-Johansen method. Cox proportional hazard models were used to demonstrate the strength of association between the independent variables and PJP risk. RESULTS: This single-center, retrospective cohort included 486 adult patients receiving bendamustine from 1 January 2006 through 1 August 2019. Most patients received bendamustine-based combination therapy (n = 461, 94.9%), and 225 (46.3%) patients completed six cycles. Rituximab was the most common concurrent agent (n = 431, 88.7%). The cumulative incidence of PJP was 1.7% (95% CI 0.8%-3.3%, at maximum follow-up of 2.5 years), after the start of bendamustine (n = 8 PJP events overall). Prior stem cell transplant, prior chemotherapy within 1 year of bendamustine, and lack of concurrent chemotherapy were associated with the development of PJP in univariate analyses. Anti-Pneumocystis prophylaxis was not significantly associated with a reduction in PJP compared to no prophylaxis (HR 0.37, 95% CI (0.05, 3.04), p = 0.36). CONCLUSIONS: Our incidence of PJP below 3.5%, the conventional threshold for prophylaxis implementation, indicates routine anti-Pneumocystis prophylaxis may not be necessary in this population. Factors indicating a high-risk population for targeted prophylaxis require further investigation.

A Five-Component Biginelli-Diels-Alder Cascade Reaction.

A new multi-component condensation was discovered during the reaction of a urea, ß-keto ester, and formaldehyde. In the presence of catalytic indium bromide, a Biginelli dihydropyrimidinone intermediate was further converted to a five-component condensation product through a formal hetero Diels-Alder reaction. The product structure was confirmed by NMR and NOE analysis, and the proposed stepwise mechanism was supported by the reaction of the Biginelli intermediate with ethyl 2-methylene-3-oxobutanoate.