Annals of Pharmacotherapy最新文献

Background: Dapsone is an alternative prophylactic agent for opportunistic infection in kidney transplant recipients (KTRs) with sufficient glucose-6-phosphate dehydrogenase levels. Potential disadvantages include increased risk for anemia and urinary tract infection (UTI) with dapsone.

Objective: The objective of this study was to compare the risks of anemia and UTI in KTRs who received prophylaxis for opportunistic infection after renal transplant with dapsone versus sulfamethoxazole-trimethoprim (SMX-TMP).

Methods: This single-center, retrospective, cohort review was conducted at a large academic health system. Adult patients who received SMX-TMP or dapsone prophylaxis after renal transplant were included. The primary outcome was risk of acute anemia within 90 days of transplant. Secondary outcomes included the risk of UTI post-transplant. Log-rank test was used for time-to-event analysis for the primary outcome.

Results: A total of 153 patients were included in the analysis. Patients were more likely to experience acute anemia while on dapsone compared with SMX-TMP (hazard ratio = 2.13, 95% confidence interval = 1.04-4.38, P = 0.04). No differences were observed in the rates of blood transfusion (14.5% vs 18.4%, P = 0.52) or use of erythropoiesis-stimulating agents (40.2% vs 48.7%, P = 0.331) between SMX-TMP and dapsone groups, respectively. The prevalence of UTI was comparable between groups (23.4% vs 23.7%, P > 0.999).

Conclusion and relevance: The risk of anemia was twofold higher in KTRs who received dapsone compared with SMX-TMP but did not appear to affect the rates of erythropoiesis-stimulating agent use or blood transfusion. There was no difference in the risk of UTI. These findings may inform agent selection and monitoring of prophylaxis for opportunistic infection in KTRs.

Background: Dalbavancin's pharmacokinetic parameters suggest obesity may affect serum and tissue concentrations, but currently there is no outcome data in the obese population with invasive infections.

Objective: The purpose of this study is to determine whether body mass index (BMI) correlates with dalbavancin 90-day treatment failure (TF) in patients with invasive infections.

Methods: A multicenter, retrospective observational study analyzed adult patients who received one or more dose of dalbavancin 1500 mg for an invasive infection at 2 community teaching hospitals. Patients admitted ≥3 times within 90 days or received ≥28 days of intravenous antibiotics prior to the initiation of dalbavancin were excluded. The primary outcome was TF at 90 days defined as the need for additional antibiotics or surgery, intolerance, readmission, death, or lost to follow-up. Logistic regression models tested the relationship between BMI and TF. A secondary analysis removed patients lost to follow-up. A conditional probability plot was generated to display the relationship of BMI and TF.

Results: Of 197 patients, 159 met inclusion criteria. Demographics included 64.8% males (n = 103), median age 46 years (34.5-60), and 48.4% (N = 77) persons who inject drugs. Bone/joint accounted for 50% (N = 80) of infections, with Staphylococcus aureus commonly isolated (N = 108, 67.9%). Sixty-eight patients experienced TF. The median BMI in the TF versus cure group was 26.0 kg/m² (21.0-30.3) and 26.0 kg/m² (23.0-30.5), P = 0.56. Significant predictors in the model included hospital site (OR = 0.28, 95% CI: 0.08-0.95) and methicillin-resistant S. aureus (OR = 3.01, 95% CI: 1.43-6.34). BMI was not a predictor of TF in the primary (OR = 1.00, 95% CI: 0.96-1.05) or secondary analysis (OR = 1.02, 95% CI: 0.97-1.07). The conditional probability plot found no relationship between BMI and TF in BMI <50 kg/m².

Conclusion and relevance: This observational study did not show an association between BMI and TF in patients treated with dalbavancin with invasive gram-positive infections.

Objective: To review the pharmacology, efficacy, and safety profile of crinecerfont as adjunctive therapy in treating classic congenital adrenal hyperplasia (CAH).

Data sources: A literature search was conducted in PubMed from January 2008 to August 2025. The relevant manuscripts, abstracts, and clinical trials (ClinivalTrials.gov) were reviewed. The keywords used were crinecerfont, CYP21A2, androstenedione, 17 hydroxyprogesterone, glucocorticoids, CAH, and clinical trials.

Data extraction: All crinecerfont-related publications, abstracts, packet inserts, and clinical trials were reviewed.

Data synthesis: Crinecerfont is a specific CRF1R antagonist used as adjunctive therapy to treat classic CAH. Crinecerfont led to over a 50% reduction in adrenocorticotropic hormone (ACTH) and 17OHP levels in both adult and pediatric participants during phase II trials. Testosterone levels decreased by 32% to 74% in adults and 61% to 76% in pediatric participants. In phase III trials, Crinecerfont reduced glucocorticoid doses by 27.3% in adults and 18% in pediatric participants (both P < 0.001). In general, crinecerfont is well tolerated with adverse effects that are mild to moderate.Relevance to patient care and clinical practice in comparison to existing drugs:Crinecerfont is an orphan drug used as adjunctive therapy for patients with classic CAH. It can effectively decrease supraphysiological levels of glucocorticoids and control androstenedione levels, thereby reducing complications related to supraphysiological glucocorticoids in classic CAH.

Conclusion: Crinecerfont is the first approved adjunctive therapy for classic CAH that effectively decreases supraphysiological glucocorticoids levels and associated symptoms.

Objective: To review the pharmacology, efficacy, and safety of revumenib (Revuforj) for relapsed or refractory (r/r) acute leukemia with a lysine methyltransferase 2A (KMT2A) gene rearrangement or translocation (KMT2Ar).

Data sources: A literature search was conducted using PubMed/MEDLINE, applicable published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and April 23, 2025. Keywords included Revuforj, revumenib, SNDX-5613, KMT2A, MLL1, and menin.

Study selection and data extraction: All English-language studies involving revumenib for r/r acute leukemia with a KMT2Ar were included.

Data synthesis: Revumenib, a protein-protein inhibitor that interrupts the interaction between the KMT2A protein and the scaffold protein menin, was granted approval by the Food and Drug Administration (FDA) for r/r acute leukemia with KMT2Ar based on a phase 2 clinical trial in adult and pediatric patients (n = 57), which reported a complete remission or complete remission with partial hematologic recovery of 22.8%. Common grade 3/4 adverse reactions reported for revumenib include infectious (febrile neutropenia 33%; infection 29%; bacterial infection 20%) and hematologic events (differentiation syndrome 13%; hemorrhage 9%; thrombosis 5%). Grade 3/4 QT prolongation, the primary dose-limiting adverse effect, was present in 12% of patients. Differentiation syndrome, related to revumenib's antileukemic effect, was observed in 29% of patients (grade 3/4: 13%; grade 5: <1%). We also include long-term follow-up for a total of 104 and 135 patients for efficacy and safety results, respectively.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:In the high-risk disease of r/r acute leukemia with KMT2Ar, given limited treatment options, revumenib appears to be a viable, novel treatment option demonstrating clinical efficacy and a manageable adverse effect profile that can be utilized as a bridge to stem cell transplant. Existing therapy options in this setting may include additional traditional chemotherapy, chimeric antigen receptor T-cell therapy (CAR-T), antibody-drug conjugates (eg, gemtuzumab, inotuzumab), bispecific T-cell engager (BiTE) therapies (eg, blinatumomab), DNA methyltransferase inhibitors (eg, azacitidine, decitabine), histone deacetylase inhibitors (eg, vorinostat, panobinostat), and BCL-2 inhibitors (venetoclax).

Conclusions: Revumenib is an innovative targeted treatment with promising activity in r/r acute leukemia with KMT2Ar.

Background: Therapeutic intensity unfractionated heparin (UFH) infusions require titration to target a therapeutic activated partial thromboplastin time (aPTT) or UFH anti-Xa. At The Johns Hopkins Hospital (JHH) and Johns Hopkins Bayview Medical Center (JHBMC), a computerized nurse-managed UFH calculator was built into the electronic health record (EHR) to improve adherence to institutional nomograms.

Objective: This study evaluated the impact of implementation of an EHR-embedded UFH calculator on nurse-managed UFH nomogram adherence.

Methods: A retrospective, observational cohort study was conducted at 2 institutions within one health system. Patients admitted to adult services who received nurse-managed UFH for at least 4 consecutive hours were included. Patients admitted between March 2019 and March 2021 constituted the pre-implementation cohort and patients admitted August 2021 through August 2023 were included in the post-implementation cohort. The primary outcomes were nurse-managed UFH nomogram adherence, management of critical aPTT results, and therapeutic aPTT achievement.

Results: A total of 2128 patients were included in the pre-implementation cohort and 2517 in the post-implementation cohort. The mean age was 61 for both the pre- and post-implementation cohorts. The post-implementation cohort experienced an increase in adherence to initial bolus dose recommendations when compared with the pre-implementation cohort (85.9% vs 92%, P < 0.001) as well as increased adherence to correct initial infusion doses (80.8% vs 95.9%, P < 0.001). Infusion dose adjustment error rates were reduced in the post-implementation cohort (4.9% vs 1.5%, P < 0.001). Fewer patients experienced nomogram nonadherence errors in the post-implementation cohort (20.2% vs 5.3%, P < 0.001). Critical aPTT nomogram adherence improved after calculator implementation for resumption at the recommended dose (72.4% vs 94.0%, P < 0.001). However, the time to therapeutic aPTT achievement was similar between pre-implementation and post-implementation cohorts.

Conclusion and relevance: A stewardship initiative to implement an EHR-embedded nurse-managed UFH calculator significantly increased adherence to nomogram-recommended initial doses and dose adjustments.

Objective: To evaluate the pharmacology, efficacy, safety, and clinical use of datopotamab deruxtecan (Dato-DXd), a recently approved trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC), in the treatment of advanced solid tumors.

Data sources: A comprehensive English-language literature search was conducted on PubMed and ClinicalTrials.gov from January 2010 through September 2025 using the search terms datopotamab, datroway, breast cancer, or nonsmall cell lung cancer.

Study selection and data extraction: Evidence was gathered from clinical trials, relevant articles, guidelines, abstracts, and package inserts.

Data synthesis: Dato-DXd received accelerated approval by the Food and Drug Administration (FDA) in 2025 for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, and epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC). In the TROPION-Breast01 trial, Dato-DXd demonstrated superior efficacy with a response rate of 36.4% versus 22.9% for chemotherapy and median progression-free survival of 6.9 versus 4.9 months. In NSCLC, TROPION-Lung01 showed a response rate of 26.4% with Dato-DXd compared with 12.8% with docetaxel. For the approved EGFR-mutant NSCLC indication, the TROPION-Lung05 trial demonstrated a response rate of 35.8% with Dato-DXd. Treatment-related adverse events included stomatitis, nausea, alopecia, and ocular events, with interstitial lung disease/pneumonitis representing the most clinically significant safety concern.

Relevance to patient care and clinical practice: The TROP2-directed ADC appears to be a viable therapeutic alternative for select patients with previously treated HR+/HER2- breast cancer or EGFR-mutant NSCLC after progression on targeted therapy.

Conclusions: Dato-DXd offers a promising treatment option for heavily pretreated patients with HR+/HER2- breast cancer and EGFR-mutant NSCLC, providing meaningful clinical benefit with a manageable safety profile. Optimal sequencing and positioning within the rapidly shifting ADC landscape requires further investigation.

Background: The 2021 Surviving Sepsis guidelines recommend which vasopressor to initiate first; however, there is a paucity of data to guide the order of vasopressor discontinuation. Retrospective studies have demonstrated an increased risk of hypotension within 24 hours if vasopressin is discontinued first; however, using a shorter timeframe may be of higher clinical relevance and more reflective of vasopressor pharmacokinetic properties.

Objective: The purpose of this study was to evaluate differences in the incidence of rebound hypotension within the first 6 hours following norepinephrine or vasopressin discontinuation in patients with septic shock.

Methods: This was a single-center, retrospective analysis of adult patients with septic shock admitted to an intensive care unit (ICU) who had either vasopressin (AVP1) or norepinephrine (NE1) discontinued first between January 1, 2021 and December 31, 2021. The major outcome was the incidence of hypotension within 6 hours of first discontinued agent. A Kaplan-Meier curve evaluated time to hypotension. Notable minor outcomes included incidence of hypotension within 12 and 24 hours, ICU length of stay (LOS), ICU mortality, and time to shock resolution.

Results: During the study period, 580 patients were evaluated for inclusion, of which 209 were included: 150 in the NE1 group and 59 in the AVP1 group. There was no difference in incidence of hypotension within 6 (54% vs 61%), 6-12 (14.7% vs 10.2%), or 12-24 (6.7% vs 10.2%) hours, ICU LOS, ICU mortality, and shock resolution between groups. The Kaplan-Meier curve showed no differences between groups in time to hypotension within 6 hours of vasopressor discontinuation (p = 0.1)Conclusion and Relevance:This is the first study to evaluate the impact of vasopressor discontinuation order in septic shock within 6 hours, finding no differences in hypotension regardless of discontinuation order. Application of this data gives reassurance the order of vasopressor discontinuation may not impact clinical outcomes.