Pharmacotherapy最新文献

Objectives: The immunomodulators tocilizumab and baricitinib improve outcomes in severely ill patients with coronavirus disease 2019 (COVID-19); however, comparative analyses of clinical outcomes related to these agents are lacking. A tocilizumab national shortage shifted treatment to baricitinib in critically ill patients, allowing for an outcome comparison in a similar population. The purpose of this study is to compare clinical outcomes in critically ill COVID-19 patients who received tocilizumab and those who received baricitinib.

Design: Retrospective, observational cohort study using generalized estimating equation models, accounting for clustering by hospital and known confounders, to estimate the proportional odds of the ordinal World Health Organization Clinical Progression Scale (WHO-CPS) score at day 14, the primary outcome. Secondary outcomes included WHO-CPS score at day 7.

Setting: Multiple hospitals within the Cleveland Clinic Health System.

Patients: Adult patients admitted for COVID-19 between January 2021 and November 2021.

Interventions: Receipt of tocilizumab, before its shortage, or baricitinib, during shortage.

Measurements and main results: In total, 507 patients were included; 217 received tocilizumab and 290 received baricitinib. Over 96% of patients required ICU admission and 98% received concomitant dexamethasone. Tocilizumab recipients had higher (worse) baseline WHO-CPS scores. After adjustment, tocilizumab use was associated with higher odds of a worse day 14 WHO-CPS score compared with baricitinib (adjusted odds ratio [OR] 1.65 [95% confidence interval (CI) 1.10-2.48]). Similarly, after adjustment, tocilizumab use was associated with higher odds of a worse day 7 WHO-CPS score (adjusted OR 1.65 [95% CI 1.22-2.24]).

Conclusions: Baricitinib use was associated with better WHO-CPS scores at day 14 and day 7 compared with tocilizumab in a cohort of critically ill patients with COVID-19. The odds of having a one unit increase in WHO-CPS score at day 14 was 71% higher with tocilizumab than baricitinib. No difference in mortality or adverse effects was noted.

Introduction: Cefazolin is the leading antibiotic used to prevent surgical site infections worldwide. Consensus guidelines recommend adjustment of the cefazolin dose above and below 120 kg without regard to body composition. Algorithms exist to repurpose radiologic data into body composition (morphomics) and inform dosing decisions in obesity.

Objectives: To compare the current standard of body weight to morphomic measurements as covariates of cefazolin pharmacokinetics and aid dose stratification of cefazolin in patients with obesity undergoing colorectal surgery.

Methods: This prospective study measured cefazolin plasma, fat, and colon tissue concentrations in colorectal surgery patients in order to develop a morphomics-informed population pharmacokinetic (PopPK) model to guide dose adjustments. A physiologically-based pharmacokinetic (PBPK) model was also constructed to inform tissue partitioning in morbidly obese patients (n = 21, body mass index ≥35 kg/m² with one or more co-morbid conditions).

Results: Morphomics and pharmacokinetic data were available in 58 patients with a median [min, max] weight and age of 95.9 [68.5, 148.8] kg and 55 [25, 79] years, respectively. The plasma-to-subcutaneous fat partition coefficient was predicted to be 0.072 and 0.060 by the PopPK and PBPK models, respectively. The estimated creatinine clearance (eCL_cr ) and body depth at the third lumbar vertebra (body depth_L3) were identified as covariates of cefazolin exposure. The probability of maintaining subcutaneous fat concentrations above 2 μg/mL for 100% of a 4-h surgical period was below 90% when eCLcr ≥105 mL/min and body depth_L3 ≥ 300 mm and less sensitive to the rate of infusion between 5 and 60 min.

Conclusions: Kidney function and morphomics were more informative than body weight as covariates of cefazolin target site exposure. Data from more diverse populations, consensus on target cefazolin exposure, and comparative studies are needed before a change in practice can be implemented.

Introduction: Vancomycin is frequently used for prolonged courses in treating osteoarticular infections despite a high rate of adverse drug events (ADE). The objective of this study was to evaluate the safety and effectiveness of transitioning to oral therapy compared to continuing parenteral vancomycin in patients with orthopedic infections.

Methods: We conducted a single-center, retrospective cohort study of patients with orthopedic infections discharged on parenteral vancomycin with a planned duration of at least 4 weeks. We compared rates of ADE while on vancomycin to rates of ADE after switching to an oral regimen. As a secondary analysis, we compared unplanned hospital readmission within 60 days and treatment failure at 1 year between patients who were transitioned to oral antibiotics within 4 weeks of vancomycin initiation and those that were not.

Results: Two hundred twenty-eight patients met the inclusion criteria. Vancomycin was associated with significantly greater toxicity compared to oral regimens. Fifty-one patients had an adverse event while on vancomycin (5.87 ADE per 1000 patient-days) while 9 patients had an adverse event on oral therapy (1.49 ADE per 1000 patient-days) (Rate difference 4.39 per 1000 patient days, 95% CI: 2.52 to 6.26 events per 1000 patient-days). In proportional hazards analysis, transition to an oral antibiotic regimen was independently associated with a lower rate of ADE (aHR 0.12, 95% CI: 0.02-0.86). Forty-one patients (18%) were transitioned to oral therapy within 4 weeks; these patients did not have an increased rate of unplanned readmission (12.2% vs 17.1%) or treatment failure (17.1% vs 21.9%).

Conclusions: Patients transitioned to oral therapy within 4 weeks of discharge had significantly fewer adverse events and similar incidences of 1-year treatment failure compared to patients maintained on parenteral vancomycin. Substituting oral antibiotics for parenteral vancomycin is a potential strategy to minimize vancomycin toxicity during the treatment of orthopedic infections.

Study objective: Levocarnitine (L-carnitine) has shown promise as a metabolic-therapeutic for septic shock, where mortality approaches 40%. However, high-dose (≥ 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high-dose L-carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre-treatment metabolites in describing drug response for patients with septic shock.

Design: Population PK analysis was done with baseline normalized concentrations using nonlinear mixed effect models in the modeling platform Monolix. Various estimates of kidney function, patient demographics, dose received, and organ dysfunction were tested as population covariates.

Data source: We leveraged serum samples and metabolomics data from a phase II trial of L-carnitine in vasopressor-dependent septic shock. Serum was collected at baseline (T0); end-of-infusion (T12); and 24, 48, and 72 h after treatment initiation.

Patients and intervention: Patients were adaptively randomized to receive intravenous L-carnitine (6 grams, 12 grams, or 18 grams) or placebo.

Measurements and main results: The final dataset included 542 serum samples from 130 patients randomized to L-carnitine. A two-compartment model with linear elimination and a fixed volume of distribution (17.1 liters) best described the data and served as a base structural model. Kidney function estimates as a covariate on the elimination rate constant (k) reliably improved model fit. Estimated glomerular filtration rate (eGFR), based on the 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation with creatinine and cystatin C, outperformed creatinine clearance (Cockcroft-Gault) and older CKD-EPI equations that use an adjustment for self-identified race.

Conclusions: High-dose L-carnitine supplementation is well-described by a two-compartment population PK model in patients with septic shock. Kidney function estimates that leverage cystatin C provided superior model fit. Future investigations into high-dose L-carnitine supplementation should consider baseline metabolic status and dose adjustments based on renal function over a fixed or weight-based dosing paradigm.

Study objective: To estimate the prevalence of potential moderate to severe drug-drug interactions (DDIs) involving nirmatrelvir/ritonavir, identify interacting medications, and evaluate risk factors associated with potential DDIs.

Design: Cross-sectional study.

Data source: Electronic health records from the National COVID Cohort Collaborative Enclave, one of the largest COVID-19 data resources in the United States.

Patients: Outpatients aged ≥18 years and started nirmatrelvir/ritonavir between December 23, 2021 and March 31, 2022.

Intervention: Nirmatrelvir/ritonavir.

Measurements: The outcome is potential moderate to severe DDIs, defined as starting interacting medications reported by National Institutes of Health 30 days before or 10 days after starting nirmatrelvir/ritonavir.

Main results: Of 3214 outpatients who started nirmatrelvir/ritonavir, the mean age was 56.8 ± 17.1 years, 39.5% were male, and 65.8% were non-Hispanic white. Overall, 521 (16.2%) were potentially exposed to at least one moderate to severe DDI, most commonly to atorvastatin (19.2% of all DDIs), hydrocodone (14.0%), or oxycodone (14.0%). After adjustment for covariates, potential DDIs were more likely among individuals who were older (odds ratio [OR] 1.16 per 10-year increase, 95% confidence interval [CI] 1.08-1.25), male (OR 1.36, CI 1.09-1.71), smokers (OR 1.38, CI 1.10-1.73), on more co-medications (OR 1.35, CI 1.31-1.39), and with a history of solid organ transplant (OR 3.63, CI 2.05-6.45).

Conclusions: One in six of individuals receiving nirmatrelvir/ritonavir were at risk of a potential moderate or severe DDI, underscoring the importance of clinical and pharmacy systems to mitigate such risks.

Study objective: The effects of the sodium-dependent glucose transporter-2 inhibitor ipragliflozin were compared with metformin in a previous study, which revealed that ipragliflozin reduced visceral fat content by 12%; however, the underlying mechanism was unclear. Therefore, this sub-analysis aimed to compare metabolomic changes associated with ipragliflozin and metformin that may contribute to their biological effects.

Design: A sub-analysis of a randomized controlled study.

Setting: Chiba University Hospital and ten hospitals in Japan.

Patients: Fifteen patients with type 2 diabetes in the ipragliflozin group and 15 patients with type 2 diabetes in the metformin group with matching characteristics, such as age, sex, baseline A1C, baseline visceral fat area, smoking status, and concomitant medication.

Interventions: Ipragliflozin 50 mg or metformin 1000 mg daily.

Measurements: The clinical data were reanalyzed, and metabolomic analysis of serum samples collected before and 24 weeks after drug administration was performed using capillary electrophoresis time-of-flight mass spectrometry.

Main results: The reduction in the mean visceral fat area after 24 weeks of treatment was significantly larger (p = 0.002) in the ipragliflozin group (-19.8%) than in the metformin group (-2.5%), as were the subcutaneous fat area and body weight. The A1C and blood glucose levels decreased in both groups. Glutamic pyruvic oxaloacetic transaminase, γ-glutamyl transferase, uric acid, and triglyceride levels decreased in the ipragliflozin group. Low-density lipoprotein cholesterol levels decreased in the metformin group. After ipragliflozin administration, N2-phenylacetylglutamine, inosine, guanosine, and 1-methyladenosine levels increased, whereas galactosamine, glucosamine, 11-aminoundecanoic acid, morpholine, and choline levels decreased. After metformin administration, metformin, hypotaurine, methionine, methyl-2-oxovaleric acid, 3-nitrotyrosine, and cyclohexylamine levels increased, whereas citrulline, octanoic acid, indole-3-acetaldehyde, and hexanoic acid levels decreased.

Conclusions: Metabolites that may affect visceral fat reduction were detected in the ipragliflozin group. Studies are required to further elucidate the underlying mechanisms.

Clozapine is an effective antipsychotic medication used for treatment-resistant schizophrenia. However, it is underutilized due to rigorous hematologic monitoring requirements and many adverse drug reactions. Publications have highlighted the occurrence of inflammatory reactions, some life-threatening, particularly during the early stages of clozapine treatment. Although guidelines have suggested monitoring for inflammatory processes during clozapine initiation, screening in clinical practice is not universal. This systematic review aimed to investigate the relationship between clozapine and inflammation and assess the importance of monitoring for inflammatory reactions. A comprehensive literature search yielded 6915 unique publication records after removal of duplicates. After a rigorous screening process, 75 publications were included in the review, which focused on three main aspects: (i) the impact of clozapine on inflammatory markers, (ii) monitoring cardiac and other organ function during clozapine-associated inflammatory processes, and (iii) monitoring non-specific signs and symptoms of inflammation. Elevated levels of C-reactive protein (CRP) and several proinflammatory cytokines have been observed in association with clozapine treatment. However, the practicality of measuring specific markers in clinical practice remains uncertain. Current evidence supports monitoring CRP levels during the first 4-8 weeks of treatment, especially to facilitate myocarditis screening. Further research is needed to establish clinically relevant CRP thresholds for intervention. The implementation of monitoring protocols during the early phase of clozapine treatment may mitigate adverse reactions and allow for continued use of clozapine. Future studies should also explore the association between clozapine-associated inflammation and pneumonia, as well as investigate the impact of inflammation on clozapine metabolism to predict the need for dose adjustment. These endeavors may facilitate the development and implementation of evidence-based guidelines for the monitoring of clozapine-associated inflammation.

Objective: To determine if a novel symptom-based alcohol withdrawal syndrome (AWS) protocol in a US Veterans cohort leads to significant clinical improvements in patient outcomes and safety.

Background: Prior studies of AWS management, oftentimes using the revised version of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) index, have demonstrated the effectiveness of symptom-triggered therapy for AWS. The Minnesota Detoxification Scale (MINDS) is an alternative to the CIWA-Ar index but remains unevaluated outside of the intensive care unit (ICU) setting. This study assesses outcomes in AWS management prior to and after the implementation of a novel MINDS-based AWS protocol (SDAWP) utilizing a revised MINDS index (MINDS-rev) in an inpatient medical ward setting.

Methods: Retrospective cohort study including encounters prior to (n = 342) and after (n = 338) the implementation of the protocol. Pre- and post-protocol encounters were selected by combinations of diagnostic codes and charting elements. Outcome measures of AWS management were obtained in both groups. The primary endpoint was median total benzodiazepine exposure. Secondary outcomes included median length of hospitalization, median duration of benzodiazepine administration, and the incidence of complications.

Results: The median total benzodiazepine exposure in the post-SDAWP group was significantly lower than the pre-SDAWP group (21.2 vs. 12.0 mg, p < 0.0001) and for a significantly shorter median duration of time (4.0 vs. 3.0 days, p < 0.0001). There was no significant difference in the median length of stay (4.0 vs. 4.0 days, p = 0.50). The incidence of delirium tremens (21 vs. 7, p = 0.01) and need for transfer to a higher level of care (33 vs. 12, p = 0.002) was significantly lower in the post-SDAWP group.

Conclusion: The SDAWP has provided significant improvements in AWS management in our institution and may potentially serve as a template for wider use in other inpatient settings.

Introduction: Vancomycin dosing tailored for newborns is challenging due to the significant influence of maturation and organ function on pharmacokinetics. Population pharmacokinetic (popPK) models can be used to improve target attainment in neonates.

Objectives: The primary objective was to derive and evaluate a popPK model of intravenous vancomycin for neonates. Second, the predictive performance of this popPK model was compared with published popPK models.

Methods: This is a retrospective cohort study of neonates admitted to the neonatal intensive care unit receiving intravenous vancomycin. A popPK model was derived with 70% of the dataset using a nonlinear mixed effects modeling method. The predictive performance of the current popPK model was validated and compared with 22 published popPK models using the remaining 30% of the dataset. Monte Carlo simulations (MCS) were performed to derive optimal dosing regimens to treat neonatal sepsis caused by coagulase-negative staphylococci (CoNS).

Results: Among 655 vancomycin courses from 448 neonates, 78% of vancomycin trough concentrations were outside target range (10-15 mg/L) for central nervous system infections and 43% were outside target range (5-12 mg/L) for other infections using the institution's vancomycin dosing. A one-compartment model best described the observed data with a mean clearance of 0.11 ± 0.03 L/kg/h and volume of distribution (V) of 1.02 ± 0.08 L/kg. Body weight (WT), postmenstrual age (PMA), and serum creatinine (SCr) were significant covariates associated with clearance (p < 0.001) and body WT was a significant covariate associated with V (p = 0.009). Our study's popPK model has similar or better accuracy and precision than other published models. MCS-derived vancomycin doses from the validated model achieved >90% target attainment for a steady state through target range of 10-15 mg/L in the majority of PMA and SCr categories (78%) to treat CoNS sepsis.

Conclusion: A vancomycin dosing guideline derived from a validated popPK model in neonates with CoNS sepsis is recommended to improve target attainment.