Mara, Kristin C

ABSTRACTItraconazole and posaconazole are frequently prescribed following transplantation to prevent and treat fungal infections. Navigating drug interactions is challenging due to these agents’ potent CYP3A4 inhibition, and literature describing concurrent apixaban, a CYP3A4 substrate, is limited. This retrospective study of cardiothoracic transplant recipients evaluates the impact of itraconazole and posaconazole on apixaban exposure and reports clinical outcomes from routine apixaban dose reduction. Institutional practice reduces apixaban to 2.5 mg twice daily with itraconazole or posaconazole and obtains apixaban therapeutic drug monitoring (TDM), expected range 34–230 ng/mL. Eighteen levels collected in 15 patients on itraconazole displayed a median [IQR] apixaban trough of 143 ng/mL [95–195]. Fifteen levels collected in 13 patients on posaconazole displayed a median [IQR] apixaban trough of 124 ng/mL [93–174]. Two major bleed events, three VTE, two stroke, and eight instances of clot resolution were identified. Reduced‐dose apixaban resulted in apixaban exposure similar to normal dosing in the general population. Apixaban TDM is encouraged for individualized dosing when administered with itraconazole and posaconazole.

OBJECTIVE The optimal dose for triazoles in pediatric patients may substantially vary given the dynamic changes in pharmacokinetics and pharmacodynamics, based on disease severity. Therapeutic drug monitoring has been a valuable tool to help guide management and avoid potential toxicities associated with treatment of invasive fungal infections (IFIs). Goal azole serum concentrations are based on specific drug, indication, and minimum inhibitory concentration when known. This study aimed to determine the optimal pediatric azole doses needed to achieve targeted serum concentrations of isavuconazole, itraconazole, posaconazole, and voriconazole. METHODS This is a single center, retrospective chart review of pediatric patients who received isavuconazole, itraconazole, posaconazole, or voriconazole between January 1, 2011, and August 31, 2021. RESULTS A total of 273 pediatric patients received isavuconazole, itraconazole, posaconazole, or voriconazole in the inpatient or outpatient setting during the study period. Of the 273 patients, only 122 met criteria for inclusion in the analysis. Eighty-three percent of patients reached a goal serum concentration. Patients younger than 12 years required a higher dose (mg/kg/day) to achieve goal serum concentrations. Patients who received an azole in the form of an oral tablet or intravenously were more likely to reach a goal concentration than those not receiving these formulations. Median time to goal concentration occurred at 20 days for isavuconazole, 34 days for itraconazole, 11 days for posaconazole, and 10 days for voriconazole. CONCLUSIONS Higher starting azole doses are needed to obtain goal concentrations quickly, especially for children younger than 12 years.

PURPOSE Cytokine release syndrome (CRS) of any grade occurs in 56%-80% of bispecific antibodies (BsAbs) used in multiple myeloma (MM). Risk mitigation strategies are required to expedite escalation of care if toxicities develop. The rarity of grade 3 or 4 CRS compels protocolized outpatient management of BsAbs as outpatient practice may avoid hospital admissions and costly resource utilization without compromising safety. MATERIALS AND METHODS Patients with MM who received BsAb step-up dosing (SUD) from August 23, 2023, to March 29, 2024, were enrolled. Baseline demographics, patient outcomes, and CRS management were reviewed to assess the safety of outpatient practice. Resource utilization was also analyzed. RESULTS In this study, 34 patients received outpatient SUD of BsAbs (teclistamab n = 17, talequetamab n = 17) with 16 remaining outpatient throughout the entire SUD period. CRS occurred in seven patients who did not require hospitalization, demonstrating the safety of outpatient management of BsAb toxicity, regardless of low-grade CRS. CRS was observed in 24 patients (maximum grade 2) and immune effector cell–associated neurotoxicity syndrome in four patients (maximum grade 3). All patients with CRS received steroids, including 12 patients at home when instructed. Tocilizumab was given to 13 patients, accounting for 18 doses. If all doses of BsAbs and tocilizumab were given outpatient, the medication margin would be $115,004 in US dollars (USD). CONCLUSION An outpatient-based practice for BsAb administration demonstrated safety and cost savings. The description of our practice and results of this study provide valuable insights into the safety, feasibility, and resource stewardship of outpatient management of BsAbs. Future research should attempt to predict and stratify CRS risk to deliver a tailored supportive strategy and continued increase of outpatient management.

Background: Cervical cancer screening with a self-collected vaginal specimen for human papillomavirus (HPV) testing was approved by the U.S. Food and Drug Administration in May 2024, offering a potential solution to declining screening rates. Objective: We aimed to assess acceptability of clinic-based vaginal specimen self-collection for HPV testing and to evaluate associations between participants’ sociodemographics and their likelihood of choosing self-collection for future screening and the overall acceptability of using the Evalyn® brush device. We also evaluated associations between specific acceptability constructs and reported likelihood to use the device in the future and overall acceptability. Methods: Following self-collection of a vaginal specimen, participants completed an electronic survey that measured constructs from the Theoretical Framework of Acceptability. Associations were assessed using logistic regressions. The study was conducted at a colposcopy clinic in the Gynecology department of a midwestern academic medical center in the United States from November 2022 through July 2023. Results: Participants ( n = 81) reported high likelihood (98% likely or very likely) of choosing in-home self-collection for future screening and unanimity on overall acceptability (100% acceptable or completely acceptable) of using the device. More affirmative responses to measures on instruction understandability, ease of device use, understanding the device is used for cervical cancer screening, and perceiving self-collection improves screening rates were associated with a higher likelihood to choose self-collection for future screenings and overall acceptability of the device (all p values <0.05). Conclusion: Vaginal specimen self-collection for HPV testing was well-received in the studied population, with high acceptability and likelihood of uptake. Implementation efforts should provide user-friendly instructions and emphasize the benefits of self-collection for cervical cancer screening, particularly among people less likely to engage with clinician-collected speculum-based screening.

Abstract Purpose Data regarding the incidence, onset, and management of complex outpatient antimicrobial therapy–induced neutropenia (COIN) are limited, and pharmacist involvement in COIN management has not been reported. This report describes the incidence, onset, and management of COIN at a large academic medical center. Methods This multisite retrospective cohort study examined adult patients undergoing serum laboratory monitoring for antimicrobials over a 4-year period. Patients receiving chemotherapy or immunosuppressants were excluded. Data collected included the antimicrobial regimen, complete blood count, duration of antimicrobial therapy until outcome occurrence, infectious syndrome, type of intervention, outcome, and pharmacist involvement. Logistic regression was used to assess risk factors for COIN incidence. The primary outcome was the incidence of COIN by antimicrobial drug. Results From 4,261 treatment episodes, 161 cases of COIN were identified (3.8% COIN incidence). The most common antimicrobials associated with COIN were intravenous piperacillin/tazobactam, cefepime, and meropenem. The majority of COIN events were attributed to a combination of at least 2 antimicrobials. Piperacillin/tazobactam was significantly associated with higher odds of developing COIN (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.04-3.34; P = 0.038), whereas ertapenem was associated with significantly lower odds of COIN (OR, 0.43; 95% CI, 0.24-0.77; P = 0.005). The median time to neutropenia diagnosis was 22 days (interquartile range, 14-29 days) from the time of inpatient antimicrobial start. Intervention for COIN occurred in 66.5% of cases, with neutrophil count recovering in 96.9% of these patients. Clinical pharmacists initiated 74.8% of interventions. Conclusion COIN can be effectively identified and managed by a multidisciplinary team reviewing routine laboratory monitoring, enabling most patients to safely complete antimicrobial treatment.

Abstract Objective: Patients with Opioid Use Disorder (OUD) are prone to Multidrug-Resistant Organism (MDRO) colonization and infections, thus at risk for worse outcomes during critical illness. Understanding the prevalence and predictors of MDRO infections is essential to optimize interventions and treatments. Design: Retrospective cohort study. Methods: The study evaluated the prevalence of MDRO isolation among adults with OUD admitted to an intensive care unit (ICU) between January 1, 2018, and July 31, 2023. It included adults admitted to an ICU with bacterial infections and positive cultures obtained within 48 hours of admission. Demographics, clinical traits, and MDRO isolation rates were analyzed using descriptive statistics, univariate methods, and Least Absolute Shrinkage and Selection Operator (LASSO) regression. Results: MDRO isolation occurred in 178 of 790 patients (22.5%), with methicillin-resistant Staphylococcus aureus as the most frequently isolated organism. LASSO regression identified housing insecurity (OR: 1.79, 95% CI 1.09–2.93, P = .022), no receipt of medications for OUD treatment (OR: 1.56, 95% CI 1.06–2.29, P = .023), positive hepatitis C virus (HCV) status (OR: 2.19, 95% CI 1.19–4.03, P = .012), and intravenous antibiotic use in the prior 90 days (OR: 1.04 per 24 h, 95% CI 1.01–1.07, P = .007) as significant predictors of MDRO isolation. Conclusions: The study highlights a high prevalence of MDRO isolation in critically ill OUD patients admitted for infection-related issues with positive cultures obtained within 48 hours of admission, influenced by factors like housing insecurity, no receipt of medications for OUD treatment, HCV status, and prior antibiotic use.

Abstract Purpose/Background Clozapine requires careful monitoring to minimize adverse reactions and optimize response. Because of variable pharmacokinetics and interpatient variability, guidelines recommend therapeutic drug monitoring (TDM), although practical guidance is limited. This study aims to characterize patient factors associated with TDM, rates of TDM use over time, turnaround times of TDM results, and influence of institutional initiatives aimed to improve TDM. Methods/Procedures A retrospective chart review was conducted at a large 2000-bed academic medical center from August 1, 2015, to November 26, 2023. Adult patients who were administered clozapine during medical or psychiatric inpatient hospitalizations were included. Data collected included patient demographics, clozapine TDM ordering, and clozapine TDM turnaround time. Yearly TDM rates were analyzed to evaluate the impact of various institutional clozapine-related initiatives on TDM practices. Results There were 679 encounters involving 334 patients; 62.7 % were men, and 84.4% were White. Younger patients were less likely to have levels drawn (odds ratio 0.98, confidence interval 0.97–0.99), while self-identified Asian patients more likely (odds ratio 7.54, confidence interval 1.60–35.42). TDM rates increased significantly over time for both medical ( P = 0.002) and psychiatric ( P < 0.001) admission types, with turnaround times improving from 66.07 hours in 2016 to 28.65 hours in 2022. Overall, TDM annual rates increased from 46.2% in 2015 to 69.6% in 2023. The time-period before and after an institutional initiative, which improved TDM turnaround time, was associated with improvements of TDM rates (36.2% vs 67.9%, P < 0.001) Conclusions This study highlights an increase in clozapine TDM use during the study period, but use remained suboptimal. Improvement of turnaround time was associated with increased TDM rates.

OBJECTIVES: Estimated glomerular filtration rate is more accurate with combined creatinine and cystatin C equations (eGFRcr-cys) than creatinine alone. This study created and evaluated a cefepime dosing nomogram based on eGFRcr-cys for initial dosing in the critically ill. DESIGN: Pharmacokinetic modeling and simulation study. SETTING: Academic medical center. PATIENTS: Critically ill adults treated with cefepime. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from 120 patients with baseline cystatin C and follow-up cefepime levels were used to develop a nomogram based on eGFRcr-cys and weight for initial cefepime dosing. The predicted proportion of patients who achieved a free cefepime concentration above the minimum inhibitory concentration of the organism for 100% of the dosing interval in the first 24 hours (100% ƒT > MIC at 24 hr) was compared between administered doses and those predicted by the nomogram doses. Overall drug exposure was estimated with the free area under the concentration time curve from 0 to 24 hours (ƒAUC0–24) and compared between administered and nomogram doses. Achievement of 100% ƒT > MIC at 24 hours was predicted to be significantly better with the nomogram compared with the administered dose (76% vs. 38%; p < 0.001). The median ƒAUC0–24 as predicted by the nomogram (666 mg·hr/L) was slightly higher than the actual ƒAUC0–24 with administered doses (612 mg·hr/L; p = 0.01), but the nomogram led to fewer ƒAUC0–24 values which were either too high (> 900) or too low (< 300) (7% vs. 20%; p = 0.004). CONCLUSIONS: Use of a cystatin C-inclusive dosing nomogram for cefepime could improve target attainment without increasing the risk of potentially toxic levels in the critically ill.

Introduction Taxane medications, paclitaxel, and docetaxel, are chemotherapy agents that have a higher incidence of reported hypersensitivity and infusion reactions. To help classify these reactions, the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) is utilized. Prophylactic medications have been used to decrease the incidence and severity of these events. At our institution, medications that patients can receive prior to the initiation of a taxane infusion are a histamine 1 receptor antagonist (H1RA), histamine 2 receptor antagonist (H2RA), a steroid or a combination of these medications. The purpose of this retrospective review was to compare the rates and severity of infusion reactions based on the timing of prophylactic medication administration in the first and second doses of taxane infusions. Methods Patients who received paclitaxel or docetaxel from January 30 th , 2022, through January 30 th , 2023, were included in the analysis. To assist in the identification of a reaction, taxane administrations were flagged for review if a rescue medication was administered after the start of a paclitaxel or docetaxel infusion. The rates and severity of infusion reactions were analyzed based on the timing of prophylactic medication administration. A sub-group analysis comparing infusion reaction characteristics between taxanes given, was performed. Results Of the 1486 taxane infusions that were completed within the year, 249 infusion reactions were confirmed and graded utilizing the NCI CTCAE. When examining the first and second doses of a taxane (N = 536), we identified 222 infusions reactions. The odds of a patient having an infusion reaction, during the first and second doses, was found to be less likely for patients given a prophylactic medication 30 min prior to receiving a taxane compared to those who did not receive a pre-medication (p = 0.037). Conclusion This multisite retrospective study showed that administration of prophylactic medications 30 to 80 min prior to the first and second infusion of a taxane was the optimal timing to decrease the likelihood of patients having an infusion reaction. No difference in the severity of the reaction was seen. Most patients were able to complete the entire infusion, regardless of what rescue medications were used following the infusion reaction.

Abstract Background Clozapine is effective for treatment-resistant schizophrenia and bipolar disorder but is often discontinued due to adverse effects. This study compared early clozapine discontinuation rates and reasons in patients with mood and psychotic disorders. Methods Data from all individuals with mood or psychotic disorders who initiated clozapine for the first time at the inpatient psychiatric unit of Mayo Clinic, Rochester, Minnesota, between 2014 and 2022 were retrospectively analyzed. Early clozapine discontinuation, defined as discontinuation within 90 days of initiation, was the primary outcome. Cox proportional hazards regression was used to assess factors associated with discontinuation. Results Of 83 patients (mood group n = 37, psychosis group n = 46), those in the mood group were older (P = 0.022) and more likely to be nonsmokers (P = 0.034). The overall 90-day clozapine discontinuation rate was 45.7%. Early discontinuation was significantly higher in the mood group than in the psychosis group (hazard ratio = 2.41, 95% confidence interval = 1.26–4.64, P = 0.008). Other factors associated with early discontinuation were female sex (P = 0.033), older age (P = 0.026), and nonsmoking (P = 0.001). In multivariable analysis, smoking status was the only factor significantly inversely associated with early clozapine discontinuation (hazard ratio = 0.47, 95% confidence interval = 0.22–0.99, P = 0.048), while diagnostic group, sex, and age did not show significant associations (all P > 0.05). Discontinuations were primarily due to adverse drug reactions in both groups. Conclusions Nearly half of the patients discontinued clozapine early, with higher rates in the mood group. Studies should further explore potential pharmacodynamic and pharmacokinetic factors associated with discontinuation, including the influence of smoking. Careful monitoring and personalized management of side effects are crucial for optimizing clozapine therapy and improving treatment outcomes.