190. Outcomes of Early Ceftaroline-based Combination Therapy for Methicillin-resistant Staphylococcus aureus Bacteremia

Background Monotherapy with vancomycin (VAN) or daptomycin (DAP) remains the guideline-driven standard of care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. While combination therapy is often utilized as salvage treatment for persistent MRSA-B, growing data suggest a potential benefit of combination therapy with ceftaroline as initial therapy for MRSA-B. In light of these data, we updated practice guidance at our institution for management of MRSA-B in March 2020 to favor initial combination therapy with ceftaroline. Herein, we present an assessment of outcomes of patients with MRSA-B initiated on early combination therapy. Methods This was a single-center, retrospective, cohort study of adult patients admitted to the University of Virginia with MRSA-B between July 1, 2018 and February 28, 2021. Patients were considered to have received combination therapy if they received VAN or DAP plus ceftaroline (CPT) within 5 days of index blood culture, and monotherapy if during that period they received VAN and/or DAP alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were also assessed. A propensity score-weighted logistic regression was conducted. A post-hoc analysis of the primary composite outcome was performed in which patients were only deemed to have received combination therapy if it was started within 72 hours. Results Of 94 patients included, 57 received monotherapy (55 VAN, 2 DAP) and 37 received combination therapy with CPT (30 VAN, 7 DAP). There was no difference between groups for the primary composite outcome in the primary analysis (OR 2.7, 95% CI 0.95-7.72) or the post-hoc analysis (OR 2.37, 95% CI 0.68-8.22). Time to microbiological cure was not different between groups (mean difference 1.47, 95% CI 0.20-2.74). Safety outcomes were similar. Conclusion In this retrospective study, there was no clear benefit or harm of early initiation of combination therapy for MRSA-B. Additional study of initial combination therapy with ceftaroline is warranted given the small number of subjects in the study presented. Disclosures All Authors: No reported disclosures

Abstract P108: Side Effects Of Initial Combination Versus Monotherapy For Patients With Hypertension

Clinical guidelines recommend initiating combination antihypertensive therapy for many patients with hypertension. However, data on the risk of side effects are limited. We evaluated side effects associated with initiating combination therapy versus monotherapy among patients with hypertension from Kaiser Permanente Southern California between 2008-2014. Patient characteristics, antihypertensive medication use, and possible side effects were collected using electronic health records. We examined the association of initial combination therapy and incidence of side effects including acute kidney injury, hypotension, injurious fall, hyperkalemia, hypokalemia, hyponatremia, or hyperuricemia using multivariable Cox Proportional hazards models. Of 164,805 patients, 44% initiated combination therapy (34% angiotensin converting enzyme inhibitor (ACEI)-thiazide diuretics (TD); 10% other combinations) and 56% initiated monotherapy (22% ACEIs; 16% TD; 11% beta blockers (BB); 7% calcium channel blockers). Incidence rates of side effects were between 3.8 for hyperkalemia to 55.5 for hypokalemia per 1000 person-yrs during median follow-up of 0.27-0.45 yrs. Initiation of ACEI-TD combination therapy was associated with a lower risk of hyperkalemia than ACEI monotherapy and a lower risk of hypokalemia than TD monotherapy ( Table ). Initiation of ACEI-TD combination therapy was associated with a higher risk of hyponatremia, hyperuricemia, and hypotension, but not associated with injurious falls when compared with other monotherapy groups. Monitoring for side effects following initiation of antihypertensive medication with combination therapy may be useful.

The Path to Effective Governance of “X” Village from the Perspective of Rural Revitalization

Rural governance is described as a continuous improvement of internal self-management in rural areas as well as the proper resolution of rural development issues. This article believes that effective rural governance must be achieved. Persist in the initial combination of autonomy, the legal system and the “three governance” system of the rule of virtue, and promote the complete and effective advancement of the rural social governance system. Continuously improve the level of spiritual civilization in rural areas through effective rural governance, and strive to promote rural revitalization.

Treatment responses and disease dynamics in patients with untreated metastatic colorectal cancer receiving bevacizumab-based sequential versus combination chemotherapy: Analysis of a phase 3 trial (AIO KRK0110, XELAVIRI study).

3571 Background: Early response parameters such as early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy endpoints and potential predictors of long-term outcome. We analyzed the association of these endpoints with bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within a randomized phase III trial. Methods: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR-image) were analyzed in the XELAVIRI-trial. Moreover, progression-free survival (PFS) and overall survival (OS) were evaluated with ETS as stratification parameter (ETS vs. no ETS) according to treatment arm, molecular subgroup, and sex. Results: 370 patients were available for analysis of early treatment response parameters. A higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination compared to the sequential therapy arm, respectively. The improvement of ETS and DpR was pronounced in the subpopulation of RAS/ BRAF wildtype patients. Male in contrast to female patients significantly benefitted from initial combination treatment in terms of median DpR (male: -40.0% vs. -22.2%; p < 0.001; female: -34.0% vs. -24.4%; p = 0.13) and rate of ETS (male: 64.8% vs. 40.2%; p < 0.001; female: 52.5% vs. 49.3%; p = 0.73). Achievement of ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Whereas the survival benefit in male patients achieving ETS was statistically significant (PFS: p < 0.001, HR 0.532 (0.409-0.692); OS: p < 0.001, HR 0.574 (0.437-0.756)), there were no significant differences in PFS (p = 0.107) and OS (p = 0.965) of female patients depending on ETS. Conclusions: In the XELAVIRI trial, initial irinotecan-based combination therapy with bevacizumab improves ETS and DpR in mCRC patients. Improvement in early response parameters appears pronounced in patients with RAS/ BRAF wildtype tumors suggesting a high sensitivity to irinotecan-based treatment. ETS was predictive of PFS and OS regardless of treatment arm. This finding was rather driven by male than female patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

Initial Combination Empagliflozin and Linagliptin Improves Kidney Fibrotic Marker in Patients With Type 2 Diabetes: A Randomized Controlled Trial

Background: Transforming growth factor-beta 1 (TGF- ß1) is a novel cytokine marker and also one of the therapeutic targets in the treatment of diabetic kidney disease. Both sodium glucose co-transporter 2 inhibitor and dipeptidyl-peptides 4 inhibitor reduce TGF- ß 1 level in animal studies, but whether it is effective in human is unknown. Objective: To evaluate the effects of combinations of empagliflozin/linagliptin, comparing with empagliflozin alone, in patients with type 2 diabetes. Material and Methods: Subjects are randomized to a combination of empagliflozin 10 mg and linagliptin 5 mg (n = 23), or empagliflozin 10 mg (n = 22) as add-on to standard treatment for 12 weeks. The primary end point is changed from baseline in serum TGF- ß1 at 12 weeks. Results: Among the 45 subjects who completed the study, mean change in TGF-ß1 was -928.2 + 1,204.2 pg/mL, and +206.6 + 592.5 pg/mL in the empagliflozin/linagliptin group and empagliflozin group, respectively (p &lt;0.001). Mean change in estimated glomerular filtration rate (eGFR) increased in the empagliflozin /linagliptin group 4.4 + 7.59 mL/min/1.73m2, whereas mean eGFR decreased in empagliflozin group -0.06 + 11.16 mL/min/1.73m2 (p =0.133). Mean change in HbA1c was -1.3 + 0.6% and -0.4 + 0.6% in empagliflozin/linagliptin and empagliflozin group, respectively (p&lt;0.001). Baseline level of eGFR significantly correlated with baseline TGF- ß1 but did not predict response to therapy. Conclusion: Initial combination empagliflozin and linagliptin may delay progression of kidney fibrosis as early as 12 weeks of treatment. Our study supports that this combination had synergistic action not only glycemic control but also beneficial in kidney protection. Keyword: transforming growth factor - ß1, diabetic kidney disease, combination empagliflozin and linagliptin

Initial combination therapy with macitentan and tadalafil in pulmonary arterial hypertension: a retrospective cohort study

Purpose: Initial combination therapy with ambrisentan and tadalafil has been demonstrated superior to either agent alone in pulmonary arterial hypertension (PAH). More recently, the OPTIMA trial showed efficacy of another combination of endothelin receptor antagonist and phosphodiesterase 5-inhibitor, macitentan and tadalafil, as initial therapy for PAH. The objective of this study was to assess the effectiveness, tolerability, and safety of macitentan and tadalafil in a real-world clinical setting.Methods: This single centre, retrospective cohort study identified adult patients newly diagnosed with PAH between January 2014 and December 2017 who were started on macitentan and tadalafil. Patients were retrospectively followed for one year. Effectiveness was evaluated via change from baseline in disease risk profile based on a validated score incorporating World Health Organization functional class, 6-minute walk distance (6MWD), B-type natriuretic peptide (BNP), and hemodynamics on follow-up right heart catheterization. Secondary endpoints included change in 6MWD, BNP, and hemodynamic variables. Drug tolerability and adverse events were assessed.Results: The cohort included 46 patients, 8 of whom (17%) did not tolerate and discontinued either macitentan or tadalafil. Median time to follow-up was 161 days (IQR 72). 42% of patients with an initially moderate or high risk disease profile improved to low risk. Secondary endpoints showed a reduction in the geometric mean of pulmonary vascular resistance of 45% (95% CI 29, 57%) and improvement in 6MWD of 88m (95% CI 27, 148m).Conclusion: In a real-world setting, macitentan and tadalafil as initial combination therapy for PAH was well tolerated and yielded clinical benefit.

Photodynamic therapy combined with anti-vascular endothelial growth factor therapy for pachychoroid neovasculopathy

This multicenter retrospective study was conducted to evaluate the 1-year treatment outcome of photodynamic therapy (PDT) combined with anti-vascular endothelial growth factor (VEGF) therapy for pachychoroid neovasculopathy (PNV). A total of 42 eyes of 42 patients with treatment-naïve PNV who were treated with PDT combined with intravitreal injections of an anti-VEGF agent (ranibizumab or aflibercept) for 1 year. All eyes showed exudative and/or hemorrhagic changes that affected the fovea at baseline. After the initial combination therapy, subfoveal choroidal thickness (SCT) and central retinal thickness (CRT) were significantly reduced and were maintained as such for 12 months (P < 0.01 in SCT and CRT). The best-corrected visual acuity (BCVA) (0.19 ± 0.30 at baseline) significantly improved at 3 months (0.15 ± 0.29, P < 0.05) and further improved at 12 months (0.10 ± 0.30, P < 0.01) when compared to that at baseline. After the initial combination therapy, 32 eyes (76.2%) required no additional treatments for 12 months. The mean number of additional PDT and intravitreal injections of anti-VEGF agents was 0.1 ± 0.3 and 0.9 ± 1.9, respectively. Of the 42 eyes included in this study, 22 eyes (52.4%) had polypoidal lesions at baseline. No significant differences in SCT, CRT, or BCVA were observed at any time points between eyes with and without polypoidal lesions. Of 20 eyes without polypoidal lesions, only 1 eye (5.0%) needed additional treatments. PNV, especially without polypoidal lesions, can be treated effectively with PDT combined with anti-VEGF therapy with few sessions.