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Background: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. Methods: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit–level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit–level COVID-19 rates. Results: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08–3.55]; P =0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32–0.99]; P =0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose ( P =0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P =0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56–1.48]; P =0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. Conclusions: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04409834.

Introduction Cardiac transplant centers are now successfully utilizing hepatitis C virus (HCV) donor hearts to increase the availability of organs now that a curative treatment is available with direct acting antivirals (DAA). We present the first described case of DAA treatment failure in a patient who received an HCV donor, nucleic acid testing (NAT) positive heart. Case Report A 65-year-old male with a mixed cardiomyopathy underwent orthotopic heart transplant with an HCV+/NAT+ heart. He seroconverted within seven days of transplant, noted by a peak HCV viral load of 7.65 log IU/mL and genotype of 1a without resistance markers. Planned initial treatment with glecaprevir/pibrentasvir (G/P) was denied by insurance. After approval for and treatment with ledipasvir/sofosbuvir (L/S) for 8 weeks, the patient's viral load was initially undetectable. However, he developed recurrent viremia 6 months after treatment completion with an HCV load of 7.40 log IU/mL with NS5A resistance due to a Y93H mutation. He was subsequently initiated on sofosbuvir/velpatasvir/voxilaprevir (S/V/V) with persistent undetectable viral loads to date at 4 months. Summary This is the first documented case of DAA treatment failure in a recipient of HCV+/NAT+ transplanted heart treated with L/S. This treatment failure was likely secondary to insufficient treatment duration. The ION-3 study demonstrated noninferiority for an 8 week treatment duration compared to 12 weeks of L/S, but at the cost of a higher relapse rate in the 8 week arm (5% vs 1%) associated with viral load of >6.78 log IU/mL. The Y93H mutation is more likely to reduce treatment efficacy in L/S as noted by a pooled resistance analysis compared to G/P, which has a failure rate of

This is a single-center retrospective observational cohort study comparing daptomycin/ceftaroline combination therapy with rifampin-adjunct therapy for the treatment of staphylococcal device infections. The results of this study support use of the daptomycin/ceftaroline as an alternative or salvage option to standard of care.

BackgroundOritavancin (ORI) is a long-acting lipoglycopeptide indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs) caused or suspected to be caused by susceptible Gram-positive (GP) pathogens.MethodsData collected from a retrospective observational program (2014–2017), Clinical and Historic Registry and Orbactiv Medical Evaluation (CHROME), describe the utilization, outcomes, and adverse events (AEs) associated with ORI in 440 patients treated at 26 US sites for ABSSSI and other GP infections.ResultsClinical success in evaluable patients receiving at least 1 dose of oritavancin was 88.1% (386/438). In a subgroup of patients who received ORI for skin and soft tissue infections (n = 401) and bacteremia (n = 7), clinical success was achieved in 89.0% and 100%, respectively. A cohort of 32 patients received 2–10 ORI doses separated by no more than 14 days for complicated GP infections. Clinical success was observed in 30 of 32 patients (93.8%), including 10 of 11 (90.9%) patients with bone and joint infections and 7 of 8 (87.5%) patients with osteomyelitis. In the safety evaluable population, the overall rate of AEs was 6.6%.ConclusionsWe describe results from a real-world program that includes the largest multicenter, retrospective, observational study in patients who received at least 1 dose of ORI for the treatment of GP infections. This study confirms that ORI is an effective, well-tolerated antibiotic used in single and multiple doses for the treatment of ABSSSIs and complicated GP infections.

Introduction Patients with end-stage heart failure eligible for orthotopic heart transplantation (OHT) exceed the number of available donor organs. With highly effective hepatitis C virus (HCV) antiviral therapy now available, HCV+ organs are increasingly utilized. We seek to describe our experience with patients receiving HCV viremic organs as compared to non-HCV transplant recipients. Methods Our center began utilizing HCV hearts in February 2018. We retrospectively reviewed baseline demographics, laboratory data and outcomes for those undergoing OHT with majority being from a viremic HCV donor. Results Twenty-three of 25 HCV recipients received hearts from NAT+ donors with 22 of 23 seroconverting within 7 days. Fifteen recipients have completed HCV treatment, with the longest duration of follow-up being 13 months. No differences in rates of rejection, hospitalizations or death were seen between non-HCV and HCV transplant patients. Discussion With the advent of available direct-acting antivirals (DAAs), viremic HCV hearts provide an opportunity to increase organ availability. Moreover, treatment for HCV in the setting of immunosuppression is well-tolerated and results in sustained viremic response. Conclusion Viremic, discordant HCV OHT can be performed in a safe and effective manner utilizing a systematic, multidisciplinary approach without an effect on short-term outcomes.

Purpose In 2017, discordant hepatitis C (HCV) heart transplantation was initiated in an attempt to expand the donor pool in the era of curable treatments for HCV with direct anti-viral therapies. However, long term outcome data in these patients remains limited. In addition, within current data published, significant variability in rates of cardiac allograft vasculopathy (CAV) along with rejection have been reported thus far. The purpose of our study is to examine long term outcomes specific to both rejection and CAV in our discordant HCV transplants in comparison to our non-HCV cohort. Methods Our center started performing discordant HCV heart transplantation in 2018. We retrospectively reviewed the baseline demographics along with outcomes, specifically rates of rejection and CAV. Results Forty-six patients underwent discordant HCV heart transplantation at our center since 2018 with 89% of those donors being nucleic acid test (NAT) positive. 80% became viremic within 7 days post transplantation. All but 3 NAT+ patients became viremic with 80% of those converting within 7 days of transplantation. All viremic patients were treated within 3 months of transplantation. Seventeen (37%) developed rejection, most frequently within 1st year (94%), with 30% within the 1st month. Rejection episodes consisted mostly of cellular rejection (> 1R) with only 30% of episodes with hemodynamic significance. In comparison, the non-HCV cohort only experienced > 1R rejection in 18% (10/55) during the same time frame with 40% of episodes being hemodynamically significant. At 1 year, 8% of patients (3 of 34) developed CAV with two of those with patients with a history of rejection within the 1st year, similar to the rate of CAV in the non-HCV cohort. One patient (2%) died within the first year due to a combination of both rejection and infection. Conclusion In this population of discordant HCV transplant patients that were predominantly NAT+, we observed a higher incidence of rejection as compared to the non-HCV cohort of the same timeframe. Thus far, overall graft function, mortality and CAV outcome have not been affected. Longer term, multi center data is necessary regarding outcomes of patients with discordant HCV transplantation.

Left ventricular assist device (LVAD) therapy remains a vital therapeutic option for patients with end-stage heart failure. Unfortunately, adverse events can occur and progress to require consideration for device exchange once the failure of medical management becomes evident, especially when heart transplantation is not possible in a timely manner. The aim of this analysis is to describe the incidence and outcomes of LVAD exchanges at our institution. Between April 2008 and May 2017, 397 patients underwent LVAD implantation, with 32 of those patients subsequently receiving exchange upon the recommendation of our multidisciplinary team due to refractory infection (n=12), device malfunction (n=5), hemolysis (n=9) and pump thrombosis (n=6). The average time from index implant to exchange was 580.6 days, with an average length of stay of 18.2 days. Survival at 3 months was 84.4%, 75.0% at 1 year and median at 8.3 years after exchange. The most common adverse events, occurring in less than 1/3 of the population, included bleeding, infection and stroke. This study suggests that LVAD exchange can be an effective and definitive mechanism for the treatment of otherwise potential fatal pump complications in highly select patients. Copyright: © 2019The Author(s). This is an open access article published under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License(https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided that the original author(s) and the publication source are credited.

Purpose Hepatitis C (HCV) organs have been increasingly utilized in solid organ transplantation since the advent of curative direct acting anti-viral (DAA) therapy. Despite the adoption of this strategy, many unanswered questions remain regarding the management of immunosuppression. In two small case series of liver transplant recipients, tacrolimus concentrations have been shown to decrease with clearance of HCV viremia. We seek to describe our experience and clinical implications in our cardiac transplant population. Methods We adopted the strategy of HCV cardiac transplantation followed by curative treatment in February of 2018. We analyzed the change in tacrolimus levels after DAA therapy in those who developed viremic HCV after receiving an HCV organ. Immunosuppression regimens were not altered for these patients from standard of care, which includes no induction therapy, corticosteroid taper by 6 months, and tacrolimus and mycophenolate mofetil as tolerated. Drug levels of tacrolimus were collected, as were clinical outcomes inclusive of infection, rejection and death. Results Twenty of twenty six NAT+/HCV+ patients experienced a decrease in tacrolimus levels with treatment, from a mean of 11.6 to a mean of 6.5 after HCV treatment. This decrease occurred towards the end of treatment and did not correspond with changes in tacrolimus dosing or other immunosuppressive agents. When compared to the non-HCV transplant population (n=37), no change in outcomes were observed. Conclusion Treatment of HCV after transplantation may be correlated with increased metabolism, resulting in more rapid clearance of tacrolimus. Careful monitoring of drug levels and graft function is recommended as HCV organs are increasingly utilized. Further investigation into the clinical implications of these metabolic changes is warranted.

Background Oritavancin (ORI) is a long-acting lipoglycopeptide antibiotic indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused or suspected to be caused by susceptible Gram-positive (GP) pathogens. Methods Data collected from a retrospective observational registry program (2014–2017), Clinical and Historic Registry and Orbactiv Medical Evaluation (CHROME), describe the utilization, outcomes, and adverse events (AEs) associated with ORI in 440 patients treated at 26 US sites. Results Mean (SD) age was 58 (16) years; 37% of patients were = 65 years old (range, 18–98). Mean (SD) BMI was 32.8 (9.0) (range, 14–65). At least 1 co-morbidity was observed in 85% of patients. Patients were treated for cellulitis (61%), wound infection (15%) or abscess (15%); 32 patients received ORI to treat other infections, such as bone and joint. Ten patients received single-dose ORI for completion of osteomyelitis therapy. Of recovered GP isolates, MRSA was the most common (46%). Infusion of ORI was mostly in infusion center settings (72%). Clinical success was 88% in the single-dose group (387 patients) and 86% in the multi-dose group (51 patients). A cohort of 32 patients received 2 to 10 ORI doses separated by no more than 14 days for complicated GP infections. Clinical success was observed in 30 of 32 patients (94%), including 10 of 11 (91%) patients with bone and joint infections and 7 of 8 (88%) patients with osteomyelitis. AEs were observed for 29 of 440 (6.6%) of patients; there was a single serious AE. Six (1.4%) patients discontinued ORI infusions due to an AE. Conclusion The CHROME program confirms that ORI is an effective and well-tolerated long-acting lipoglycopeptide antibiotic for the treatment of a range of Gram-positive infections. Disclosures All authors: No reported disclosures.

Purpose Patients with end-stage heart failure eligible for orthotopic heart transplantation (OHT) exceeds the number of available donor organs. With the introduction of curative medications for hepatitis C (HCV), these hearts are now being utilized in an effort to expand organ availability. The safety and feasibility of these organs in OHT has been previously described; however, many of the donor hearts were HCV immune and non-viremic. We seek to describe our experience with patients receiving HCV viremic organs. Methods St. Vincent Hospital in Indianapolis, IN began utilizing HCV hearts for OHT in February 2018. We retrospectively reviewed baseline demographics, laboratory data and outcomes for those undergoing OHT from a viremic donor. Results Basic information and results are reported in Tables 1 and 2. To date, 5 recipients have completed HCV treatment, with the longest duration of follow up currently 8 months. The average seroconversion time of a viremic heart was 7 days. Compared to non-HCV donors during this same timeframe, there was no increase in infection, rejection or number of hospitalizations. Additionally, patients completing antiviral treatment have had a sustained virologic response, with another 2 currently undergoing treatment and the final 3 awaiting insurance approval to initiate treatment. Conclusion In our early experience, we have demonstrated the feasibility of utilizing viremic HCV donor hearts for organ transplantation , thereby increasing the pool of available donors for patients that may not have otherwise received an organ. Further analysis of discordant HCV transplantation's financial impact is currently ongoing.

Influenza remains a frequent cause of hospitalization and death during the winter season. Since early in March of 2018, influenza B has been more frequently reported than influenza A. While the incidence of myocarditis from influenza is rare (from 0-11%), the severity of illness can include

We have previously shown that CTL and NK cells rapidly down regulate perforin mRNA and become functionally inactive within 4-6 hr after exposure to sensitive target cells (TC). We report here for the first time that CTL also down regulate perforin mRNA upon exposure to resistant, but binding, TC. When three separate human MHC-restricted CTL lines were exposed to resistant TC, perforin mRNA was rapidly degraded. Removal of both extracellular Ca++ and Mg++ prevented perforin message down regulation, whereas removal of Ca++ alone did not, indicating that CTL:TC binding was required. Unlike the response of CTL exposed to sensitive TC, resistant TC did not trigger serine esterase (SE) release, suggesting distinct signalling pathways for perforin mRNA down regulation and granule exocytosis. Moreover, using western analysis, we showed that there was limited (< 10%) perforin protein release after CTL:TC interaction, suggesting that CTL loss of lytic activity after exposure to sensitive TC is not due to massive depletion of perforin. Treatment of CTL with mAb to CD2, CD3, CD2 + CD3, CD8, Class I and LFA-1 did not induce perforin mRNA down regulation. Furthermore, mAb to CD2, CD3, CD8, Class I, Class II, CD54 and LFA-1 did not block TC-mediated perforin mRNA down regulation although lysis of TC was inhibited.