First Clinical Cases of OXA-48-Producing Klebsiella pneumoniae in Peru

Background: Carbapenemase-producing Enterobacteriaceae (CPE) represents a global public health concern and systemic infections associated with OXA-48 carbapenemase are increasingly being reported in Latin America. Here, we present the first 2 cases of systemic infections by OXA-48-Producing Klebsiella pneumoniae in Peru. A favorable clinical response was observed after targeted treatment with colistin as a backbone.

POS0407 PROTEOMICS ANALYSIS COMPARING THE MODE OF ACTION OF UPADACITINIB BETWEEN NON-BIOLOGIC-DMARD-IR AND BIOLOGIC-DMARD-IR PsA PATIENTS IDENTIFIES DISTINCT PATHOGENIC PATHWAYS IN THE SELECT-PsA 1 AND SELECT-PsA 2 PHASE 3 STUDIES

Background:Treatment of non-biologic-DMARD-IR1 (DMARD-IR) and biologic-DMARD-IR2 (bio-IR) PsA patients with upadacitinib (UPA) at 15 mg QD, an oral JAK1 selective inhibitor, resulted in significant improvement in signs and symptoms compared to placebo.Objectives:Using a pre-defined set of inflammation-related plasma protein biomarkers (pBM), to explore immunological pathway modulation by UPA 15 mg QD in PsA patients with active disease despite treatment with non-biologic or biologic DMARDs in the context of clinical response vs. non-response to treatment.Methods:Patients from the SELECT-PsA 1 (DMARD-IR) and the SELECT-PsA 2 (bio-IR) studies were randomly selected (PBO, n=100; UPA 15 mg QD, n=100 for each study). The levels of 92 inflammation related protein biomarkers (pBM) were analyzed using a multiplexed Proximity Extension Assay platform in plasma samples collected at baseline, week 2, and 12; change from baseline in protein levels was expressed as Log2 Fold Change; a Repeated Measure Mixed Linear Model was used to identify pBM modulated by UPA compared to Baseline, and those differentially modulated between responders (R) and non-responders (NR) according to ACR50, PASDAS Minimal Disease Activity, and PASI75 at week 12. Correlation of disease activity measures with relative levels of pBM were derived using Pearson’s correlation; PASI score was transformed as Log10 (x+1) prior to the analysis. Functional pathway prediction was performed in silico with a commercial distributed software.Results:At baseline, the relative levels of 37 pBM correlated with at least one baseline disease activity measure, with a marked positive correlation of IL6 with musculoskeletal end points (PASDAS and DAS28CRP), and a strong positive correlation of IL20, IL17A, IL17C, and TGFA with baseline PASI.At the single pBM-level, treatment with UPA 15 mg QD resulted in a down modulation of pBM associated with T cells, myeloid cells, and IFN-, IL6-, and TNF-related pathways in both DMARD-IR and bio-IR PsA patients. Overall effects of UPA on single pBMs were broadly similar between DMARD-IR and bio-IR patients. However, analysis of pBMs differentially modulated by UPA in R vs NR indicated that favorable clinical response (achievement of ACR50, PASDAS MDA, and PASI75) in DMARD-IR patients was associated with the down modulation of pBMs predicted to be linked to IFN, IL10, IL17, IL22, and IL27 pathways; while favorable clinical response in bio-IR patients was associated with the down modulation of multiple pBM predicted to be linked to the IL17, IL23, and IL1 pathways.Conclusion:UPA effects in both DMARD-IR and bio-IR PsA patients likely stem from the direct and indirect inhibition of multiple biological pathways belonging to the adaptive and innate immune systems. Responder/Non-Responder analysis suggests a possible shift from a TH1 biased biology in DMARD-IR PsA patients to a more TH17 biased biology in bio-IR PsA patients. This apparent change in the disease biology of PsA patients after inadequate response to prior therapy could be attributed to the actual alteration of the disease biology, treatment outcome-based patient selection, or both. Considering the clinical efficacy of UPA in both DMARD-IR and bio-IR PsA patients, this observation highlights the importance of targeting multiple pathways with drugs such as UPA for the treatment of a broad range of PsA patients.References:[1]McInnes, I. et al. Annals of the Rheumatic Diseases 79, 16-17 (2020).[2]Mease, P.J. et al.Annals of the Rheumatic Diseases, annrheumdis-2020-218870 (2020).Acknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.Disclosure of Interests:Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Jaclyn Anderson Shareholder of: AbbVie, Employee of: AbbVie, Koji Kato Shareholder of: AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB Pharma, Grant/research support from: AbbVie, Amgen, UCB

Critical Neonatal Congenital Heart Disease – a Rare Complication after Successful Surgical Correction

Pulmonary arterial hypertension (PAH) is a rare but severe complication that should be investigated in patients diagnosed with transposition of the great arteries who have undergone neonatal arterial switch operation. Early diagnosis and aggressive combination therapy for PAH could help to improve survival in these patients. We report a favorable clinical response 6 months after the initiation of vasodilator therapy in a pediatric case with transposition of the great arteries, successfully repaired in the neonatal period, who developed pulmonary arterial hypertension at the age of 5 years.

Abstract 15258: Higer Unipolar Voltage at Cell Injection Sites Correlates With Better Outcomes After Transendocardial Cd34 + Cell Transplantation in Patients With Chronic Heart Failure

Introduction: The evidence supporting the impact of electroanatomic guidance in defining the targets for transendocardial cell injections in chronic heart failure (CHF) remains inconclusive. Hypothesis: We evaluated a correlation between electroanatomic properties of the myocardium at the cell injection sites and clinical response to CD34 + cell therapy in CHF patients. Methods: We enrolled 131 consecutive patients with CHF and LVEF<40% undergoing CD34 + cell therapy at a single study site. All patients received bone-marrow stimulation with filgrastim for 5 days; CD34 + cells were collected by apheresis and injected transendocardialy (80x10 6 cells per patient). Target injection sites were defined by electroanatomical mapping as myocardial areas with unipolar voltage >8.3mV and local linear shortening <6%. Favorable clinical response was defined as an increase in LVEF≥5% between baseline and 6 months follow-up. Results: Of 131 patients 69 (53%) displayed a favorable clinical response (Group A) and 62 (47%) patients failed to respond to cell therapy (Group B). At baseline, the groups did not differ in gender (male: 89% in Group A vs. 84% in Group B, P=0.45), age (53±12 years vs. 55±11 years, P=0.25), CHF etiology (ischemic: 22% vs. 32%, P=0.17), LVEF (29±6% vs. 32±7%, P=0.06), or LVEDD (6.3±1.2 cm vs. 6.7±1.0 cm, P=0.10). Patients in Group A had lower baseline creatinine (81±20 μmol/L vs. 92±24 μmol/L in Group B, P=0.005), and lower levels of NT-proBNP (931±1078 pg/mL vs. 2716±2716, P=0.001). The number of cell injections in Groups A and B was comparable (17.3±2.6 injections vs. 17.6±3.5 injections, P=0.60). When analyzing the electroanatomical properties at cell injection sites, we found significantly higher unipolar voltage in Group A (11.2±3.7 mV vs. 9.5±2.6 mV in Group B, P=0.005). However, we found no differences in injection site local linear shortening between the groups (2.7±3.9% in Group A vs. 3.4±3.4 in group B, P=0.56). Conclusions: In CHF patients, higher unipolar voltage at the cell injection sites appears to correlate with better clinical response to transendocardial CD34 + cell therapy. Thus, cell injections guided by measurements of myocardial viability may offer an advantage over blind cell injection strategies in this patient population.

A noninferiority cluster-randomized controlled trial on antibiotic postprescription review and authorization by trained general pharmacists and infectious disease clinical fellows

ObjectiveWe compared the effectiveness of antibiotic postprescription review and authorization (PPRA) determined by infectious disease (ID) clinical fellows with that of trained general pharmacists.MethodsWe conducted a noninferiority cluster-randomized controlled trial in 6 general medical wards at Siriraj Hospital in Bangkok, Thailand. Three wards were randomly assigned to the intervention (ie, the pharmacist PPRA group), and another 3 wards were assigned to the control (ie, the fellow PPRA group). We enrolled all patients in the study wards who received 1 or more doses of the targeted antibiotics: piperacillin/tazobactam, imipenem/cilastatin, and meropenem. The noninferiority margin was 10% for the favorable clinical response and 1.5 defined daily doses (DDDs) for the targeted antibiotics.ResultsWe enrolled 303 patients in the pharmacist PPRA group and 307 patients in the ID fellow PPRA group. The baseline and clinical characteristics were similar in the 2 groups. The difference in the favorable response of patients who received the targeted antibiotics (ie, the pharmacist PPRA group minus the fellow PPRA group) was 5.15% (95% confidence interval [CI], –2.69% to 12.98%); the difference in the DDD of targeted antibiotic use (ie, the pharmacist PPRA group minus the fellow PPRA group) was 0.62 (95% CI, –1.57 to 2.82). We observed no significant difference in the DDD of overall antibiotics, 28-day mortality, 28-day ID-related mortality, favorable microbiological outcome, or antibiotic-associated complications.ConclusionsWe confirmed the noninferiority of pharmacist PPRA in terms of favorable clinical response; however, noninferiority in targeted antibiotic consumption could not be established. Therefore, using trained general pharmacists rather than ID clinical fellows could be an alternative in a resource-limited setting.Clinical trials registration: clinicaltrials.gov identifier: NCT 01797133

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

Key Points Clinical response of SSc patients after AHSCT is associated with thymic and bone marrow rebounds. Responder patients showed higher Treg and Breg counts and lower pre-/post-AHSCT TCR repertoire overlap than nonresponder patients.