Pharmacotherapy最新文献

Chronic kidney disease (CKD) is a significant global health challenge that impacts both patients and the health care system. This systematic review aims to evaluate the efficacy and safety of emerging therapeutic strategies for CKD management, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), finerenone, sacubitril/valsartan, and potassium binders. We conducted searches in databases including PubMed, Scopus, CINAHL Complete, and Web of Science Core Collection to identify experimental and observational studies pertaining to each of these agents. Included studies were those that enrolled adult patients with CKD who evaluated SGLT2i, GLP-1RA, finerenone, sacubitril/valsartan, and potassium binders compared to other medications or placebo and evaluated renal-related outcomes as a primary or secondary outcome. Methodological quality and risk of bias were assessed using the Cochrane Risk of Bias (version 2) tool for experimental studies and ROBINS-I for observational studies. After screening 2135 unique studies, 138 studies were eligible for this review. These studies describe a substantial and growing body of evidence focused on improving the management of CKD beyond renin-angiotensin system inhibitors (RASi), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). Currently, SGLT2i have demonstrated consistent benefits with large effect sizes in preventing the progression of CKD, solidifying this class as a first-line treatment along with RASi. Subsequent consideration for GLP-1RA, finerenone, and sacubitril/valsartan should be dependent on patient-specific comorbidities, while potassium binders may allow for longer use of RASi.

Objectives: HIV has been shown to persist in the central nervous system (CNS) in persons on antiretroviral therapy (ART). Our objective was to use pharmacokinetic (PK) modeling to estimate cerebrospinal fluid (CSF) exposure from time-variant concentrations of various antiretrovirals of ART regimens and to standardize CSF metrics, including maximum concentration [C_MAX], area under the curve [AUC], and trough [C_Trough].

Methods: Advancing Clinical Therapeutics Globally (ACTG) A5321 is a prospective cohort study of HIV-1 reservoirs in persons with HIV. Plasma and CSF antiretroviral (ARV) concentrations were measured in 74 participants who were receiving ART. PK modeling (Pmetrics) was performed for nine ARVs. Relative CSF penetration for each ARV was estimated by comparing CSF C_MAX and AUC to plasma C_MAX and AUC (i.e., C_MAXmethod and AUC_method). The CSF C_Trough for each ARV was compared with in vitro literature values of HIV inhibitory concentration values (IC_{50, 90, or 95}).

Results: Emtricitabine exhibited the highest median relative CSF penetration (C_MAXmethod, 46.3%; AUC_method, 72%) and dolutegravir had the lowest CSF penetration (C_MAXmethod, 0.57%; AUC_method, 0.57%). Tenofovir, lamivudine, atazanavir, and raltegravir had median estimated CSF C_Trough concentrations less than IC_{50, 90, or 95}. Interparticipant variability of relative CSF penetration based on exposures ranged from 160% for lamivudine to approximately 9% for dolutegravir.

Conclusions: PK modeling successfully standardized ARV CSF concentrations to a given time point (i.e., C_MAX or C_Trough) to allow estimation of CSF penetration. This approach provides uniformity for the assessment of exposure, for the estimation of whether desired therapeutic drug goals are obtained in the CSF, and for further studies to investigate whether CSF exposure metrics calculated using this method are associated with measures of HIV persistence.

Background: Vancomycin guidelines recommend area-under-the-curve (AUC) therapeutic monitoring for patients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections. No recommendations exist for patients with non-severe staphylococcal infections or those with other Gram-positive infections. AUC-based vancomycin dosing can be resource-intensive and may not be necessary for all patients.

Methods: New institutional guidelines for vancomycin dosing were implemented across an eight-hospital health system in 2023. The new guidelines recommended either AUC or trough-based dosing depending on the severity of the infection and the likelihood of MRSA. Adult patient encounters with at least one vancomycin administration were compared retrospectively 6 months pre-implementation and 6 months post-implementation. Cumulative vancomycin dose, administrations, and serum levels were assessed. The rate of acute kidney injury (AKI) was compared in a subgroup of patient encounters with four or more administrations. Pharmacist time saved using a blended approach compared to a uniform AUC dosing guideline was estimated based on the number of patients receiving trough-based dosing in the post-implementation group.

Results: A total of 8155 patient encounters were included in the analysis (3916 pre-implementation, 4239 post-implementation). The primary outcome of median cumulative vancomycin dose (mg) was 500 mg lower in the post-implementation group (3000 mg pre-implementation vs 2500 mg post-implementation, Odds ratio [OR] 0.94 95% confidence interval [CI] 0.90-0.97, p < 0.001). Patients in the post-implementation group were significantly less likely to have vancomycin serum levels drawn (OR 0.86; 95% CI 0.78, 0.96, p = 0.005). A subgroup of patient encounters receiving four or more vancomycin administrations included 2483 patient encounters (1251 pre-implementation, 1232 post-implementation). AKI occurred in 120 (9.6%) cases pre-implementation and 89 (7.2%) cases post-implementation. The risk of AKI was significantly lower post-implementation (OR 0.73; 95% CI 0.55, 0.98, p = 0.038). Estimated pharmacist time saved was between 2229 to 5201 min, equating to an estimated $16,851.24 to $39,319.56 saved over 6 months, with blended vancomycin dosing.

Conclusion: In this large multi-hospital cohort, the implementation of a blended dosing method using a majority of AUC-based dosing reduced cumulative vancomycin doses, serum levels, and AKI. Including trough recommendations for patients with less severe infections and non-MRSA, Gram-positive pathogens may have saved significant pharmacist time and associated costs compared to a uniform AUC dosing policy. This study further highlights the sizeable amount of unnecessary vancomycin use with a corresponding low incidence of severe MRSA infections.

Antibiotics constitute the majority of prescriptions for women during pregnancy. Common bacterial infections, including urinary tract infections, skin and soft tissue infections, and upper and lower respiratory tract infections, are expected in pregnancy, similar to the general public. These infections carry additional risks to both the woman and fetus; thus, antibiotics are often prescribed. Antibiotics, like other drugs, are not benign and may carry additional risks to the fetus beyond commonly encountered adverse drug events seen across most patient populations. Since 2014, 19 new antibiotics have been approved by the United States Food and Drug Administration. Additionally, in 2018, the previously held pregnancy category rating expired, and all manufacturers' labeling was updated with new narrative language reflecting safety in pregnancy, lactation, and males and females of reproductive potential. This review provides a comprehensive summary of available data and an update to the 2015 publication regarding the safe use of antibiotics in pregnancy. The primary focus of this review is on newly approved antibiotics, along with any additional published evidence on previously reviewed antibiotics. Data on lactation or antiviral or antifungal use in pregnancy are not included. Clinicians should remain updated on current available evidence and vigilant to provide safe and effective antibiotic decision-making in pregnant women.

Introduction: With recent clinical implementation of tirzepatide, patients with type 2 diabetes mellitus (T2DM) are transitioning from glucagon-like peptide 1 receptor agonists (GLP-1 RA) to a dual gastric inhibitory polypeptide (GIP)/GLP-1 RA-like tirzepatide. Limited literature is available for insulin dose adjustments for patients concurrently using insulin during this transition. In clinical trials, tirzepatide has shown greater glycated hemoglobin (A1c) reduction and glucose-lowering effects compared to GLP-1 RAs, such as semaglutide, suggesting a potential elevated risk of hypoglycemia without proactive insulin adjustments.

Objectives: The primary objective of this study was to assess the percent change in daily insulin requirements 6 months after transitioning patients from GLP-1 RAs to tirzepatide.

Methods: This retrospective cohort study includes patients with T2DM who transitioned from a GLP-1 RA to tirzepatide while concurrently using insulin therapy. Patient-reported doses of insulin and study medications were collected by chart review by investigators, along with baseline demographics and adverse effects as additional endpoints.

Results: Sixty-six patients were included. The median insulin dose reduced from 101 units at baseline to 71 units after 6 months, with a median decrease of 9.5 units (p < 0.001). The median percent change in insulin dose was -9.2%. Patients with a baseline A1c of 8.0% or lower required a larger decrease in insulin compared to patients with a higher baseline A1c (-22.6% vs. 0%, p = 0.018). The intensity of GLP-1 RA and tirzepatide, determined by agent and dose, did not show a difference in insulin requirements (p = 0.279 and p = 0.317, respectively). Hypoglycemia occurred in eight patients (12.1%).

Conclusion: Patients require a reduction in insulin when transitioning from GLP-1 RAs to tirzepatide, especially if baseline A1c is less than or equal to 8.0%. Larger, comparative studies need to be performed to provide specific recommendations for various doses and product types of incretin receptor agonists.

Introduction: The prevalence of exposure to supratherapeutic doses or contraindicated medications based on renal dosing criteria, also known as potentially inappropriately prescribed medications (PIPM), is currently unknown among patients on peritoneal dialysis (PD). The primary objective of this study was to evaluate the prevalence of PIPM in the first year of PD among Medicare patients in the United States.

Methods: This was a retrospective longitudinal cohort analysis of patients starting PD in 2018 in the United States Renal Data System database. Inclusion criteria were patients >65 years of age, continuously enrolled in Medicare Part D for 12 months, and prescribed ≥1 medication(s) at the start of dialysis. Prevalence of exposure to PIPM was determined at the start of dialysis and quarterly over 1 year. Logistic regression evaluated which patient characteristics (age, sex, race, Hispanic ethnicity, rurality, social deprivation index (SDI), United States region, polypharmacy, and diagnosis of diabetes and hypertension) were associated with exposure to ≥1 PIPM at the start of PD.

Results: There were 3760 patients included, and 28% were exposed to PIPM at the start of dialysis, and 21.8% were still exposed by the end of the first year. Patients with ≥4 versus <4 medications were at 2.8-14.1 times the odds of being exposed to PIPM (<0.001). Other key characteristics associated with exposure to PIPM were age ≥85 versus <75 years (adjusted odds ratio [aOR] 0.67, 95% confidence interval [CI] 0.48-0.95 p = 0.03), living in the South versus the Northeast (aOR 1.30 95% CI 1.02-1.66, p = 0.04), and diagnosis of diabetes (aOR 1.52, 95% CI 1.29-1.78, p < 0.001).

Conclusion: This study found that approximately 20%-30% of patients receiving PD were exposed to PIPM from 2018 to 2019. Results from this study support the need to create medication management programs to decrease exposure to PIPM.

Osteoarthritis (OA) is the most common form of arthritis, affecting over 500 million people globally. Current treatments are primarily symptom-focused, with no approved therapies to halt disease progression. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), widely used in type 2 diabetes (T2D) and obesity, demonstrate significant weight loss and glucose-lowering effects and have been shown to possess anti-inflammatory properties. Given the central role of inflammation and metabolic dysfunction in OA, this review examines the potential utility of GLP-1 RAs in OA management, focusing on both indirect effects, such as weight reduction, and possible direct effects on inflammatory pathways and cartilage preservation. Clinical studies suggest that GLP-1 RAs may benefit people with OA by reducing weight, improving glycemic control, and modulating inflammatory markers relevant to OA progression. Notable findings include significant weight loss and pain reduction in people with knee OA (KOA) treated with semaglutide in the STEP-9 trial. In other studies, GLP-1 RAs have shown potential to lower oxidative stress and pro-inflammatory cytokines, such as tumor necrosis factor (TNF-α) and interleukin (IL)-6, with reductions in OA-related pain and functional impairment observed in some cohorts. However, results vary, with some studies showing limited effects, potentially linked to the degree of weight loss achieved. Although some studies report variability in pain relief, likely influenced by the degree of weight loss achieved, GLP-1 RAs have shown overall promise in reducing both OA symptoms and markers associated with disease progression. This emerging evidence supports the utility of GLP-1 RAs as a potential disease-modifying option for OA, offering a dual benefit in metabolic and joint health. Future research should focus on establishing the long-term efficacy and safety and elucidating the mechanism by which GLP-1 RAs influence OA pathology.

Introduction: Heart failure (HF) affects more than 6 million adults in the United States, contributing to substantial morbidity, mortality, and health care costs. Despite advances in medical care, many medications can exacerbate HF, yet their prevalence of use remains unknown. This study examined the national use of prescription medications that could exacerbate HF in adults with self-reported HF.

Methods: We analyzed data from US adults with self-reported HF in the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020. Medications known to exacerbate HF, identified from HF guidelines, were documented through pill bottle reviews. Weighted estimates were used to calculate prevalence overall and by sex, race and ethnicity, and level of evidence for avoidance. Multivariable logistic regression models calculated adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for the use of these high-risk medications by sex and race and ethnicity.

Results: A total of 687 participants, representing 5.2 million U.S. adults with HF after applying sampling weights, were included (mean age, 66.1 [95% CI 64.9, 67.4] years; 50.4% female [95% CI 45.9%, 55.0%]). Overall, 14.5% (95% CI 10.4%, 19.5%; n = 92) of adults with HF were prescribed at least one medication known to exacerbate HF, with the most common being diltiazem, meloxicam, and ibuprofen. Use of these medications was not significantly different by sex nor by race and ethnicity. Of these medications, 21.7% (95% CI 10.7%, 38.8%) had level A evidence warning against use, and 78.3% (95% CI 61.2%, 89.3%) had B level evidence.

Conclusion: Over one-seventh of U.S. adults with HF were likely to have been prescribed medications that could exacerbate the condition, underscoring the need to optimize care. Reducing high-risk medication use may mitigate HF exacerbations and improve outcomes in this vulnerable population.

Introduction: The use of serum creatinine (SCr) for drug dosing has significant limitations and is influenced by many non-kidney factors. Cystatin C (cysC) is an alternative or additional marker of kidney function that is less affected by non-kidney factors. Although cysC may be useful in hospitalized patients, the use of cysC to calculate drug dosing in critically ill patients has been incompletely investigated.

Objective: The objective of this study was to determine the rate of discordance in estimated glomerular filtration rate (eGFR) between SCr-based calculations and SCr/cysC-based calculations that affect drug dosing in critically ill patients.

Methods: This was a single-center, retrospective, observational cohort study at an academic medical center including critically ill adult patients admitted in 2023 with SCr and cysC ordered. Data were collected via chart review. Demographic data were analyzed via descriptive statistics. Discordance, defined as the percentage of times at which there is at least one discrepancy in kidney dosing for a medication using Cockcroft-Gault (CG) creatinine clearance versus Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR creatinine-cystatin C (eGFRcr-cys) equations, was analyzed via Wilcoxon matched pair signed ranked sum. eGFR calculations were normalized for patients' body surface area for comparison.

Results: The study population included 232 patients (53.02% female; mean age 58.7 +/- 14.9 years; with 62.5% in medical, 23.28% in surgical, and 8.62% in neurological intensive care) with a median SCr of 0.94 mg/dL IQR [0.57-1.58] and median cysC of 1.92 mg/L IQR [1.27-2.77]. The median clearance rates were 68.5 mL/min (45.3-111.5) for CG and 53.9 mL/min (30.9-80.7) for CKD-EPI eGFRcr-cys; p < 0.001. The discordance rate across all study drugs was 32.3% (75/232). The four most common study drugs demonstrating discordance were cefepime 40.6% (52/128), vancomycin 38.3% (46/120), levetiracetam 35.1% (13/37), and piperacillin/tazobactam 11.6% (5/43).

Conclusion: Clinically significant discordance exists between SCr and SCr/cysC-based estimates of kidney function. This study established a discordance rate, as defined by drug dosing, of 32.3% in adult patients admitted to the ICU.