Pharmacotherapy最新文献

Introduction: Treatment of infections in patients with burn injuries is challenging due to altered antimicrobial pharmacokinetics. Continuous infusion β-lactam therapy may be a useful antimicrobial stewardship strategy to improve pharmacodynamic target attainment in this population.

Case summaries: This report highlights the use of continuous infusion ceftolozane/tazobactam (C/T) in two patients with extensive total body surface area (TBSA) burns, suspected augmented renal clearance (ARC), and bloodstream infections caused by Pseudomonas aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa). Both patients received C/T 9 g/day via continuous infusion. Minimum inhibitory concentrations (MIC) of C/T were 8/4 and 4/4 μg/mL in Cases 1 and 2, respectively.

Discussion: Despite similar patient characteristics, average free plasma ceftolozane concentrations were 41.6 mg/L in Case 1 and 22.8 mg/L in Case 2. Measured free concentrations exceeded 4 times the MIC for 100% of each 24-h infusion (fT > 4xMIC), and bacteremia was successfully cleared in each case.

Conclusion: These cases highlight the variability of drug exposure in patients with extensive TBSA burn injuries and support continuous infusion β-lactam therapy as a proactive strategy to optimize pharmacodynamic target attainment when pharmacokinetics are unpredictable.

The use and misuse of opioids has surged in the past decade, with nearly half of the users being female. Although opioid use is lower among pregnant women, trends mirror the general population. While pediatric exposures largely occur through prescriptions. This review presents a novel landscape analysis of pharmacology knowledge gaps in opioids in the maternal and pediatric populations. We queried PubMed for studies on 27 opioids, focusing on pharmacokinetics (PK), and pharmacoepidemiology (PE) or clinical trials (CT) in maternal and pediatric populations. English-language publications were included, and data were synthesized to identify gaps. Additionally, MarketScan claims data and United States Food and Drug Administration (FDA) drug labels were analyzed to compare scientific evidence, opioid prescriptions/orders, and FDA recommendations. Morphine, fentanyl, methadone, and buprenorphine are the most researched opioids in PK and PE/CT literature in both populations, but hydrocodone, oxycodone, and codeine are the most prescribed. Nine opioids lack FDA labels, and four of the 18 labeled drugs lack any human data. Hydrocodone, oxycodone, and codeine labels include lactation-focused PK information, with some pediatric clinical data for the latter two. Seven opioids lack PK and PE/CT studies in the maternal population, and PK research is absent for seven opioids, and PE/CT data is lacking for eight opioids in the pediatric population. PK studies often focus on labor, delivery, and lactation accompanied by neonatal data, whereas pregnancy research mainly occurs in PE studies. In pediatric populations, study types are evenly distributed among children, but PE studies focus more on adolescents. Drug concentration is the most reported parameter in PK studies, and neonatal opioid withdrawal syndrome (NOWS) is a key outcome in both PK and PE studies. NOWS is also researched more using real-world data, whereas neurodevelopmental outcomes are often captured in prospective observational studies. There is substantial disparity between the most commonly researched and prescribed opioids. In particular, the opioid pharmacology knowledge gaps are larger in pregnant women and for the highly prescribed opioids hydrocodone and oxycodone. The limited human data in FDA labels underscores the need for additional studies. Studies using real-world data can potentially help address these gaps.

Objective: To investigate the risk of aortic aneurysm or dissection associated with fluoroquinolone (FQ) prescription compared to macrolides in German routine health care data in order to replicate the recent study (Pharmacotherapy 2023;43:883) extending the results by contributing evidence for six additional broad-spectrum antibiotic classes as active comparators.

Design: Cohort study in active comparator new user design comparing FQ with macrolides, tetracyclines, penicillins with extended spectrum, penicillins and beta-lactamase inhibitor combinations, second- and third-generation cephalosporins, sulfonamide and trimethoprim combinations, and lincosamides.

Setting: German statutory health insurance, the "Allgemeine Ortskrankenkasse" (AOK), January 2013 to December 2019.

Participants: Adults with at least one new prescription fill for FQ or active comparator antibiotics. New users were defined as individuals without antibiotic prescription fills, aortic aneurysm or dissection diagnoses, and hospitalization within 365 days prior to the cohort entry date. Users of FQ and active comparators were matched by nearest neighbor 1:1 propensity score matching.

Main outcome measures: Incident inpatient aortic aneurysm or dissection was observed within a 60-day risk window. In sensitivity analyses, an extended risk window of 90 days was applied, and specific FQ agents, dosages, and diagnoses were stratified.

Results: FQ episodes were associated with an increased risk for aortic aneurysm or dissection compared to macrolides (aHR = 1.52 [1.33; 1.74]), which replicates the risk estimate of Garg et al. (aHR = 1.34 [1.17; 1.54]). This association was robust in a 90-day risk window and for ciprofloxacin, levofloxacin, and moxifloxacin. Moxifloxacin comprised the greatest risk of aortic aneurysm or dissection compared to macrolides (aHR = 2.13 [1.64; 2.77]). Moreover, we observed similar associations when comparing FQ to tetracyclines, penicillins with extended spectrum, cephalosporins, and lincosamides (aHR = 1.86 [1.54; 2.24], aHR = 1.45 [1.28; 1.65], aHR = 1.23 [1.10; 1.37], and aHR = 1.73 [1.43; 2.11]), respectively.

Conclusion: In a German cohort study, FQ use was associated with a 52% increased risk for aortic aneurysm or dissection within 60 days compared with macrolide use. The risk of FQ-associated aortic aneurysm or dissection compared to macrolides can be replicated in German routine health care data. Extending the analysis, we provided new insights that the effect size may depend on the chosen AC.

Background: Rapid assessment of diuretic efficacy is necessary in the treatment of acute decompensated heart failure. European guidelines advocate for the use of spot urinary sodium measurements, but recent data suggest urinary chloride is the better marker. Laboratory turnaround, however, delays clinical decision-making. We tackle this by using a commercially available chloride urinary dipstick to estimate sodium and measure chloride.

Methods: This was a prospective pilot study involving patients hospitalized at the University of Michigan for acute decompensated heart failure (ADHF) with an indication for intravenous diuresis; patients were eligible for enrollment within 24 h of admission. Patients with end-stage kidney disease or receiving continuous loop diuretic infusions or thiazide-type diuretics were excluded. A spot urine sample was collected after the loop diuretic dose. A chloride dipstick was used, and results were compared against laboratory-obtained measurements of urinary chloride and sodium.

Results: In a total of 22 patients (mean age 62.2 ± 11.8 years, 50% female, and LVEF 31.8 ± 17.4%), dipstick chloride concentrations correlated highly with laboratory-measured urine chloride (r = 0.98, p < 0.001) with slight overestimation across the physiological range and with laboratory-measured urine sodium (r = 0.86, p < 0.001), although with greater variation. Dipstick interpretation preceded laboratory results by a median of 136 minutes (IQR 103-170, p < 0.001).

Conclusions: The chloride dipstick rapidly and accurately assessed urine chloride almost 2 h faster than traditional laboratory output in patients undergoing diuresis for ADHF. It may be a new tool to evaluate loop diuretic treatment for ADHF. However, more studies are needed to assess its impacts on clinical outcomes.

Background: Posaconazole is an example of a highly protein-bound drug (>98%) in which therapeutic drug monitoring (TDM) is commonplace. Total drug concentration is typically measured, and in the setting of hypoalbuminemia, total concentrations are lower despite no anticipated change in unbound concentration. Data support that unbound posaconazole concentration is responsible for antifungal activity and, in theory, is responsible for adverse effects that are dose-related. However, the therapeutic range of posaconazole is expressed as total concentration. The objective of this study was to investigate the use of an equation to correct posaconazole concentrations for albumin concentration as a surrogate for measurement of unbound concentration.

Methods: Data on unbound and total posaconazole concentration were acquired retrospectively from a study of posaconazole pharmacokinetics in critically ill patients. The relationship between total and unbound concentration was explored with and without albumin as a covariate using linear regression. Correction equations were used to normalize total concentration to an albumin concentration of 4.4 g/dL.

Results: A total of 78 pairs of total and unbound concentrations were available. Total and unbound posaconazole concentrations were determined using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The median fraction unbound was 0.00645 (interquartile range of 0.00331-0.00794). Albumin concentration plays a highly significant role in the interpretation of TDM results. In a patient with hypoalbuminemia, a corrected concentration (C_corr) = C_t/(0.01 + 0.99·Alb/4.4), where C_t is the total concentration and Alb is the albumin concentration in units of g/dL, is suggested. This equation can be further simplified to C_sim = C_t·4.4/Alb, where C_sim is a close approximation of C_corr.

Conclusions: Hypoalbuminemia is associated with lower total concentrations of posaconazole; however, the "active" unbound concentration is not expected to systematically change. As a result, total posaconazole concentrations in the therapeutic range for patients with hypoalbuminemia are more likely to be associated with toxicity, especially when doses are increased to achieve "therapeutic" concentrations.

Objective: The Anticholinergic Drug Scale (ADS) is a commonly used measure of anticholinergic exposure. This study describes an expanded and revised version of the ADS (rADS) and its relationship with cultured cell-based serum anticholinergic activity (cSAA) and cognitive measures.

Study participants: Adults aged 60 years and older with mild cognitive impairment (MCI), remitted major depressive disorder (rMDD), or both, participate in the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study.

Study design: Cross-sectional investigation of data from the PACt-MD study.

Measures: The rADS includes ratings for 1047 distinct products, about twice as many as the originally published scale; previously published ratings were revised for 40 drugs. Total rADS scores were calculated as sums of ratings of all drugs taken by participants; cSAA was measured in the participants' sera; cognitive performance included measures of executive function, language, processing speed, verbal memory, visuospatial memory, working memory, and an overall composite score.

Statistical analysis: The relationship between rADS total scores and cSAA was examined using a Spearman rank correlation coefficient. Relationships between rADS total scores and cognitive performance measures were explored in multivariable linear regression models.

Results: The sample included 310 participants (mean [standard deviation] age: 72 (6) years; 61.6% were women, and 81.6% had MCI [with or without rMDD]). Total rADS scores were positively correlated with cSAA (Spearman's correlation coefficient: 0.178, p = 0.0016). Total rADS scores were not significantly associated with cognitive performance.

Conclusions: The revised scale is recommended as a replacement for the original ADS since it includes ratings for more drugs and was significantly, albeit weakly, associated with cSAA, similar to previous findings using the original ADS.

Objectives: To compare outcomes of oral switch versus intravenous antibiotics for the treatment of carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) infections at hospital discharge.

Methods: Institutional review board approved, retrospective cohort of adults infected with CRE or CRPA who received oral switch or intravenous antibiotics at hospital discharge from January 1, 2017, to April 30, 2024. Patients were included if they were eligible for oral switch and infected with an isolate susceptible to one or more oral antibiotics; non-bacteremic urinary tract infections were excluded. The primary outcome was 30-day clinical success at end of therapy, defined as lack of infection-related hospitalization, infection-related recurrence, or change/escalation of therapy. Secondary outcomes included hospital length of stay (LOS) and 30-day all-cause mortality from end of therapy.

Results: Fifty-five patients were included; 51% received oral switch antibiotics and 49% received intravenous antibiotics. Thirty-three percent of patients had CRE, 67% had CRPA, and 38% of cultures were polymicrobial. The most common infection types were pneumonia (33%), intra-abdominal (26%), and bone/joint (22%). The median (interquartile range [IQR]) duration of outpatient therapy was 12 (6-25) days versus 20 (4-34) days for the oral switch and intravenous antibiotic groups, respectively (p = 0.341). 30-day clinical success was 61% in the oral switch and 48% in the intravenous antibiotic groups (p = 0.349); the median (IQR) hospital LOS for the oral switch and intravenous antibiotic groups was 14 (9-25) days and 16 (9-49) days, respectively (p = 0.165); 30-day mortality was 4% in the oral switch group and 15% in the intravenous antibiotic group (p = 0.193).

Conclusion: A limited sample of patients who received oral switch antibiotics had similar outcomes to intravenous outpatient treatment of carbapenem-resistant organisms, with a shorter hospital LOS.

Background: Several previous studies have identified a potential risk of acute kidney injury (AKI) associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, based on adverse event reports. However, recent European observational studies have shown conflicting results.

Objective: To evaluate the risk of AKI in patients with type 2 diabetes (T2DM) who were treated with dapagliflozin compared with sitagliptin.

Method: We conducted a retrospective cohort study on patients with T2DM who were newly prescribed dapagliflozin or sitagliptin between September 1, 2014, and June 30, 2021, using the nationwide National Health Insurance Review and Assessment (HIRA) Service database in Korea. Propensity scores were estimated using a multivariable logistic regression model, and matching was performed at a 1:1 ratio to balance the dapagliflozin and sitagliptin groups. The outcome of interest was the occurrence of AKI hospitalization 90 days post-exposure, captured by a validated algorithm based on the International Classification of Diseases 10th Revision (ICD-10) code: N17. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using a Cox proportional hazards model.

Results: Among 94,977 dapagliflozin users matched to sitagliptin users, AKI events occurred in 132 dapagliflozin users versus 198 sitagliptin users, with incidence rates of 2.92 and 8.93 per 1000 person-years, respectively. The risk of AKI events was 34% lower in dapagliflozin users (HR: 0.66, 95% CI: 0.53-0.83) compared with sitagliptin users. This protective effect remained consistent in sensitivity analyses.

Conclusion: Contrary to the United States Food and Drug Administration's safety warning, our findings suggest that dapagliflozin may have a protective effect against AKI in patients with T2DM. This is consistent with recent findings from European post-marketing safety studies and may serve as supportive evidence.

Background: Midodrine has been primarily studied as an adjunctive oral therapy to reduce the need for vasopressors in intensive care units (ICU). Nonetheless, the available results evaluating midodrine as an adjuvant therapy in the treatment of septic shock are limited and inconclusive. This study aims to evaluate the efficacy of midodrine, specifically focusing on its effect on mortality outcomes in patients with septic shock.

Methods: This was an open-label randomized controlled trial. Patients with septic shock (n = 100) were randomized to either the control group, who received intravenous norepinephrine, or the midodrine group, who received intravenous norepinephrine and midodrine 10 mg every 8 h. The primary outcome was the 28-day in-hospital mortality. Secondary outcomes were 7-day ICU mortality, average dose of norepinephrine, duration of intravenous norepinephrine, ICU length of stay (LOS), and in-hospital LOS.

Results: The 28-day mortality rate was 68% in the control group compared to 54% in the midodrine group (risk difference -14% (95% confidence interval (CI)) -32.9% to 4.9%). Similarly, the 7-day ICU mortality rate was 56% in the control group and 42% in the midodrine group (risk difference -14% (95% CI -33.4% to 5.4%)). The average intravenous norepinephrine dose in the midodrine group was significantly lower compared to the control group (mean difference 0.06 (95% CI 0.01-0.11), p = 0.002). However, midodrine did not have a significant impact on the duration of intravenous norepinephrine use (mean difference 0.66 (95% CI -0.56 to 1.88)). Midodrine did not significantly shorten the course of hospitalization. There was no significant difference in median ICU LOS between the control group and the midodrine group (4 vs. 5 days, respectively).

Conclusion: The findings did not demonstrate a significant reduction in mortality with adjuvant midodrine use in the treatment of septic shock. Midodrine appears to reduce the need for vasopressors. However, our findings did not support that midodrine shortens the duration of vasopressor use nor the course of hospitalization for patients with septic shock.