Pharmacotherapy最新文献

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.

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.

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: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are breakthrough medicines for obesity treatment and have rapidly gained widespread clinical application. Although GLP-1RAs are generally not associated with drug-drug interactions (DDIs) via drug metabolism or transporter pathways, their effects on reduced gastrointestinal (GI) motility could influence the pharmacokinetics of coadministered oral medications.

Objectives: This study uses physiologically based pharmacokinetic (PBPK) modeling to evaluate the DDI potential of GLP-1RA-induced GI motility delays.

Methods: Using Certara's Simcyp™ Simulator V23, we modeled the pharmacokinetics of atorvastatin, metformin, metoprolol, ethinyl estradiol, and digoxin in a virtual cohort of obese adults (n = 1000). GLP-1RA-related gastric emptying delays were simulated based on capsule endoscopy data from liraglutide-treated patients. Results were compared with clinical data from semaglutide and liraglutide users. Additionally, exploratory analyses were conducted on frequently coadministered drugs identified from the 2022 Medical Expenditure Panel Survey, including rosuvastatin and dabigatran.

Results: GLP-1RA-induced gastric emptying delays led to increased area under the concentration-time curve (AUC) and prolonged time to maximum concentration (Tmax) for several medications. The model outputs for rosuvastatin, valsartan, and dabigatran indicate increases in AUC by 64%, 90%, and 205%, respectively. Dabigatran, a narrow therapeutic index anticoagulant, exhibited the most significant changes, raising potential concerns of higher drug exposure.

Conclusions: PBPK modeling suggests that GLP-1RAs can influence the pharmacokinetics of oral medications by delaying gastric emptying, potentially leading to clinically relevant DDIs. While further clinical validation and pharmacovigilance is needed, these findings highlight the importance of PBPK tools in predicting and potentially mitigating risks associated with GLP-1RA use.