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

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.

P017 Out of outlier status: local observations from the National Early Inflammatory Arthritis Audit

Background/Aims The National Early Inflammatory Arthritis Audit (NEIAA) provides a powerful lever for driving up quality. Rheumatology services benchmark care against NICE quality standards (QS) 33. Notifications are sent out quarterly to Trusts at risk of being an outlier and outliers are identified in the annual report. After being named as an outlier, this project describes our journey to improve compliance against QS2 (patients are seen in a rheumatology clinic within 3 weeks of referral and QS3 (patients with rheumatoid arthritis (RA) are started on DMARDs within 6 weeks of referral). Methods Data submitted to the NEIAA online tool during year one were downloaded for analysis. Results were presented to the Rheumatology Multi-Disciplinary Team, the patient pathway was mapped, driver diagrams were developed by the team and areas for improvement identified and changes implemented. Data from year two were downloaded for comparison. Results In total 530 patients were recruited to the audit: 262 in year 1 and 268 in year 2. 77 (29%) in year 1 and 73 (27%) in year 2 had confirmed RA and were included in this analysis. All patients had a baseline form completed, and 61 (86%) and 56 (77%) had a 3-month follow-up form completed for year 1 and 2, respectively. The demographics were very similar for years 1 and 2. In year 1, 10% of all patients were seen within 3 weeks of being referred and 7% in the RA cohort started DMARD therapy within 6 weeks of referral. This compared to 54% and 56%, respectively, in year 2. Changes implemented relating to QS2 included referral guidelines for primary care, prompts when requesting rheumatoid factor and CCP antibodies and changes to the wording of antibody reports, increased triage capacity, simplifying the booking process and increased new appointment capacity (additional consultant, upskilling extended scope practitioner). QS3 changes implemented included increasing drug education and monitoring clinic capacity and improved sign-posting to National Rheumatoid Arthritis Society. Initial combination therapy was more prevalent in sero-positive patients and those with a high DAS28 during both years. In year 1, disease activity at baseline vs. 3 months was: remission/low disease activity in 8% vs. 54%, moderate in 45% vs. 39% and high in 47% vs. 7%. In year 2, rates at baseline vs. 3 months were: remission/low disease activity 12% vs. 69%, moderate in 60% vs. 25% and high in 28% vs. 6%. Conclusion Significant changes have been made which have resulted in an improvement in performance against QS2 and 3. Disease activity at baseline was lower, potentially as a result of seeing patients sooner and this has resulted in better outcomes for patients at 3 months. Ongoing data collection will allow the team to determine outcomes at 12 months. Disclosure E. MacPhie: Other; EM is the secretary of the North West Rheumatology Club, these regional meetings have been funding by an unrestricted educational grant from UCB and are now sponsored by Abbvie. L. Ashcroft: None. J. Brazendale: None. N. Foreman: None. S. Gilbert: None. C. Greenall: None. S. Horton: None. I. Lewis: None. A. Madan: None. C. Rao: None. S. Fish: None.

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.

Advantages and limitations of initial combination therapy in pulmonary arterial hypertension patients in Russia

Pulmonary arterial hypertension (PAH) is severe and often times rapidly progressive disease with fatal outcome. The concept of initial combination of PAH-specific therapies in high risk patients at baseline was first described in the European guidelines on pulmonary hypertension (PH) in 2009, and in low or intermediate risk patients at baseline in 2015. Interestingly, that in Cologne Experts Consensus, and then in the 6th World Symposium on PH medical community started considering initial combination therapy as one of the most important pillars in PAH treatment algorithms in 2018. As of August 2020, as many as 8 formulations of 7 reference PAH-specific drugs are licensed for medical use in the Russian Federation. On top of that, 6 abbreviated drugs (generics) have also become available few years ago. Unfortunately, intravenous and subcutaneous prostacyclin analogs (PCA) and tadalafil are not approved for PH patients treatment in the Russian Federation. In this narrative review paper we attempted to describe studies on initial dual combination therapy with PAH-specific drugs registered in Russia, i.e. ambrisentan and riociguat, macitentan and riociguat, macitentan and sildenafil in low or intermediate risk patients at baseline, as well as iloprost inhaled and sildenafil, iloprost inhaled and bosentan in high risk patients. Some beneficial pharmacological effects due to the synergy between ambrisentan plus riociguat, and inhaled iloprost plus sildenafil appear to be interesting and require further clinical confirmation. Other initial combinations of PAH-specific agents require large-scale clinical trials as well.

Identification of predictors of response to initial oral combination therapy in WHO-functional class II or III PAH patients: a post-hoc analysis of the AMBITION study

Background AMBITION Study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil (COMB) compared with monotherapy of either agent (MONO), and the results contributed to the ESC/ERS guidelines recommending initial combination therapy in PAH patients with low and intermediate risk. However, predictors of response to initial oral combination therapy to identify PAH patients who benefit most from it have not been assessed. Purpose To identify potential predictors of response to initial combination therapy with ambrisentan and tadalafil (COMB) in PAH patients with WHO-FC II or III in the AMBITION study. Methods We examined 302 COMB patients from the modified intention to treat (mITT) population enrolled in the AMBITION study (n=605). The mITT population includes PAH patients with risk factors related to heart failure with preserved ejection fraction (Ex-PAS) who were excluded from the primary analysis set (PAS). A responder (i.e. event-free subject) was defined as not having a clinical failure event. Univariate and multivariate analyses were performed to identify the factors associated with responders. Multivariate logistic regression analysis was used to determine independent risk for each factor that showed a significant difference between cohorts by interactive backward selection. Odds ratio (OR), 95% confidence intervals (CIs) and p-values are presented. Results Univariate analysis showed that responders tended to be lower age, female, typical PAH (i.e. PAS), absence of coronary artery disease, non-use of oxygen therapy, and have better baseline parameters (i.e., lower NT-proBNP, longer 6-minute walk distance, low Borg index, high SaO2, WHO-FC II). A multivariate logistic regression analysis showed that female gender (OR=2.669, 95% CI: 1.291–5.518, P=0.0081), use of aldosterone antagonist diuretics (OR=2.535, 95% CI: 1.027–6.257, P=0.0436), lower log NT-proBNP (OR=0.704, 95% CI: 0.524–0.944, P=0.0190), and longer 6-minute walk distance (OR=1.006, 95% CI: 1.002–1.010, P=0.0039) were independent predictors of response to initial combination therapy. Conclusion These findings suggest that initial combination therapy with ambrisentan and tadalafil is beneficial, especially in less severe typical PAH patients. It also demonstrates that there is a potential contributing factor (i.e. use of aldosterone antagonist diuretics) which is not listed in the risk assessment table of the ESC/ERS guidelines. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): AMBITION study was funded by GlaxoSmithKline (GSK; study number 112565; trial registration number: NCT01178073) and Gilead Sciences, Inc. This analysis was funded by both companies.