Vancomycin (VAN) and daptomycin (DAP) are approved as a monotherapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. A regimen of daptomycin plus ceftaroline (DAP+CPT) has shown promise in published case series of MRSA salvage therapy, but no comparative data exist to compare up-front DAP+CPT head-to-head therapy versus standard monotherapy as an initial treatment.

Objectives: Dysregulated neutrophil and platelet interactions mediate immunothrombosis and cause lung injury in coronavirus disease 2019. IV immunoglobulin modulates neutrophil activation through FcγRIII binding. We hypothesized that early therapy with IV immunoglobulin would abrogate immunothrombosis and improve oxygenation and reduce progression to mechanical ventilation in coronavirus disease 2019 pneumonia. Design: Prospective randomized open label. Setting: Inpatient hospital. Patients and Intervention: Hypoxic subjects with coronavirus disease 2019 pneumonia were randomized 1:1 to receive standard of care plus IV immunoglobulin 0.5 g/kg/d with methylprednisolone 40 mg 30 minutes before infusion for 3 days versus standard of care alone. Main Results: Sixteen subjects received IV immunoglobulin and 17 standard of care. Median ages were 51 and 58 years for standard of care and IV immunoglobulin, respectively. Acute Physiology and Chronic Health Evaluation II and Charlson comorbidity scores were similar for IV immunoglobulin and standard of care. Seven standard of care versus two IV immunoglobulin subjects required mechanical ventilation (p = 0.12, Fisher exact test). Among subjects with A-a gradient of greater than 200 mm Hg at enrollment, the IV immunoglobulin group showed: 1) a lower rate of progression to requiring mechanical ventilation (2/14 vs 7/12, p = 0.038 Fisher exact test), 2) shorter median hospital length of stay (11 vs 19 d, p = 0.01 Mann Whitney U test), 3) shorter median ICU stay (2.5 vs 12.5 d, p = 0.006 Mann Whitey U test), and 4) greater improvement in Pao 2/Fio 2 at 7 days (median [range] change from time of enrollment +131 [+35 to +330] vs +44·5 [–115 to +157], p = 0.01, Mann Whitney U test) than standard of care. Pao 2/Fio 2 improvement at day 7 was significantly less for the standard of care patients who received glucocorticoid therapy than those in the IV immunoglobulin arm (p = 0.0057, Mann Whiney U test). Conclusions: This pilot study showed that IV immunoglobulin significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in coronavirus disease 2019 patients with A-a gradient greater than 200 mm Hg. A phase 3 multicenter randomized double-blinded clinical trial is under way to validate these findings.

Background. Interventions mitigating progression to mechanical ventilation in COVID-19 would markedly improve outcome and reduce healthcare utilization. We hypothesized that immunomodulation with IVIG would improve oxygenation and reduce length of hospital stay and progression to mechanical ventilation in COVID-19 pneumonia. Methods. Patients with COVID-19 were randomized 1:1 to prospectively receive standard of care (SOC) plus intravenous immunoglobulin (IVIG) 0.5 g/kg/day x 3 days with methylprednisolone 40 mg 30 minutes before infusion versus SOC alone. Results. 16 subjects received IVIG plus SOC and 17 SOC alone. The median age was 51 years for SOC and 58 years for IVIG. APACHE II scores and Charlson comorbidity indices were similar for IVIG and SOC (median 7.5 vs 7 and 2 for both, respectively). Seven SOC versus 2 IVIG subjects required mechanical ventilation (p=0.12, Fisher exact test). Among subjects with A-a gradient of >200 mm Hg at enrollment, the IVIG group showed i) a lower rate of progression to requiring mechanical ventilation (2/14 vs 7/12, p=0.038 Fisher exact test), ii) shorter median hospital length of stay (11 vs 19 days, p=0.01 Mann Whitney U), iii) shorter median ICU stay (2.5 vs 12.5 days, p=0.006 Mann Whitey U), and iv) greater improvement in PaO2/FiO2 at 7 days (median [range] change from time of enrollment +131 [+35 to +330] vs +44.5 [-115 to +157], p=0.01, Mann Whitney-U test) than SOC. Conclusion. This pilot prospective randomized study comprising largely of Latino patients showed that IVIG significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in COVID-19 patients with A-a gradient >200 mm Hg.

SUMMARYOrf virus has a worldwide distribution among sheep and goats. The hypersensitivity reaction erythema multiforme (EM) is a known complication of orf infection in humans; however, its occurrence is poorly understood and has not been extensively reviewed. We present two unrelated cases of orf-associated EM, and a review of the literature, highlighting important clinical, epidemiological and immunological aspects of this condition. Orf and its associated complications can occur in rural areas, as well as urban settings, where it is less well-known, through religious or cultural practices involving animal slaughter. Obtaining a history of animal exposures from patients with lesions suspicious for orf and secondary skin eruptions can guide diagnosis and identification of the inciting immune stimulus. Determining the pathophysiology and relative contribution of host and viral factors contributing to EM and other orf-associated hypersensitivity reactions could facilitate the identification of risk factors and inform treatment decisions.

Background Daptomycin and ceftaroline (DAP-CPT) have been used for persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB), but have rarely been compared with other therapies. This study provides an exploratory analysis of patients placed on DAP-CPT vs standard of care (SOC) for MRSAB. Methods This is a retrospective, matched cohort study MRSAB patients at 4 hospitals in the United States. Patients receiving DAP-CPT for ≥72 hours at any point in therapy were matched 2:1 when possible, 1:1 otherwise, to SOC, first by infection source, then age and renal function. SOC was empiric treatment with vancomycin or daptomycin and any subsequent combination antibiotic(s), except for DAP-CPT. Results Fifty-eight patients received DAP-CPT with 113 matched SOC. Ninety-six percent of SOC received vancomycin, and 56% (63/113) escalated therapy at least once in the treatment course. Twenty-four patients received DAP-CPT within 72 hours of index culture; 2 (8.3%) died within 30 days vs 14.2% (16/113) with SOC (P > .05). Subgroup analysis identified numerically lower mortality in DAP-CPT patients with a Charlson comorbidity index ≥3, endovascular source, and receipt of DAP-CPT within 72 hours of index culture. The median MRSAB duration was 9.3 vs 4.8 days for DAP-CPT and SOC, respectively. DAP-CPT was initiated on day 6 on average; after receipt of DAP-CPT, MRSAB duration was 3.3 days. Conclusions DAP-CPT treatment is often delayed in MRSAB. Combination therapy may be more beneficial if initiated earlier, particularly in patients at higher risk for mortality. Blinded, randomized, prospective studies are needed to eliminate selection bias inherent in retrospective analyses when examining DAP-CPT vs SOC.

A recurrent case of left-sided endocarditis caused by high-level aminoglycoside-resistant Enterococcus faecalis was successfully treated with ceftaroline and daptomycin. This combination demonstrated excellent synergy in vitro. Mechanistically, ceftaroline enhanced binding of daptomycin to the cell membrane and sensitized E. faecalis to killing by human cathelicidin LL-37, a cationic innate host defense peptide. Daptomycin plus ceftaroline may be considered in salvage therapy in E. faecalis endovascular infections and requires further study.A 63-year-old man with a past medical history significant for hypertension presented with fevers for 1 month. The patient received levofloxacin and doxycycline for presumed prostatitis. Physical examination revealed a grade 2 systolic murmur and grade 1 diastolic murmur. Blood cultures were positive for Enterococcus faecalis. The patient was admitted to the hospital and started on ampicillin-sulbactam and gentamicin. The white blood cell count (WBC) was 10,100 cells/mm 3 , hemoglobin was 14 g/dl, and the chest X-ray was normal. Repeat blood cultures showed ampicillin-susceptible E. faecalis with high-level gentamicin resistance (HLGR). A transesophageal echocardiogram revealed a 5-mm vegetation on the noncoronary cusp of the aortic valve. On the third hospital day, gentamicin was discontinued and ceftriaxone at 1 g intravenously (i.v.) every 12 h (q12h) was started, along with ampicillin at 2 g i.v. q4h. Blood cultures became negative after 96 h of treatment. The patient remained asymptomatic thereafter, and blood cultures remained negative during and after 6 weeks of therapy.Two weeks after completion of therapy, the patient presented to the emergency department with a temperature of 39.2°C. Examination revealed a grade 3 systolic heart murmur and grade 1 diastolic murmur. A transesophageal echocardiogram showed severe aortic regurgitation and an increase in the size of the vegetation to 10 mm. E. faecalis was recovered from blood cultures without any change from the previous susceptibility profile. Ampicillin at 12 g, continuous infusion over 24 h, and ceftriaxone at 1 g i.v. q12h were started initially. On hospital day 2, ceftriaxone was switched to daptomycin at 8 mg/kg i.v. daily, based on prior data showing synergy between these antibiotics against enterococci and successful clinical use (1, 2). The patient became afebrile after 24 h of therapy. Blood cultures that were repeated after 48 and 96 h of daptomycin plus ampicillin therapy turned positive for the same isolate after 4 and 3 days, respectively.Based on unpublished in vitro observations in our laboratory, which have demonstrated synergy between daptomycin and ceftaroline against several clinical bloodstream isolates of E. faecalis and Enterococcus faecium, and a published report of synergy between daptomycin and ceftaroline against MRSA (3), ampicillin was discontinued and ceftaroline at 600 mg i.v. every 8 h was added to the daptomycin treatment, and there was successful clearance of the bacteremia. The patient...

Cefazolin and ertapenem combination therapy was used successfully to salvage 11 cases (6 endocarditis) of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including immediate clearance (≤24 hours) in 8 cases. While in vitro synergy was modest, cefazolin plus ertapenem exhibited synergistic action in a rat model of MSSA endocarditis. The combination of cefazolin and ertapenem provides potent in vivo activity against MSSA beyond what is predicted in vitro and warrants further clinical study in the treatment of refractory MSSA bacteremia and endocarditis.

Introduction Despite considerable scientific debate, there have been no prospective clinical studies on the effects of angiotensin II receptor blockers (ARBs) on the course of COVID-19 infection. Losartan is the ARB that was chosen to be tested in this study. Methods Patients with COVID-19 and mild hypoxia (receipt of ≤ 3 L/min O 2 by nasal cannula) admitted to three hospitals were randomized in a 1:1 ratio within 72 h of SARS-CoV-2 nucleic acid testing confirmation to prospectively receive standard of care (SOC) alone or SOC plus losartan 12.5 mg orally every 12 h for 10 days or until hospital discharge, with the option to titrate upward dependent on blood pressure tolerability. Primary composite endpoint was receipt of mechanical ventilation or death before receiving ventilation. Subjects were followed until discharge to home or until an endpoint was met in the hospital. Results Sixteen subjects received an ARB plus SOC and 15 subjects received SOC alone. The median age was 53 years for both groups. Median time from hospital admission to study enrollment was 2 days (range 1–6) for the ARB group and 2 days (range 1–4) for the SOC group. Mean Charlson comorbidity index was 2 for both groups. One subject in each group achieved the composite endpoint. Conclusion This small prospective randomized open-label study showed no clinically significant impacts of ARB therapy in mildly hypoxemic patients hospitalized with COVID-19 early in the pandemic. A larger prospective randomized placebo-controlled trial would be needed to confirm these findings or capture less pronounced effects and probably should focus on outpatients earlier in disease course. Trial Registration clinicaltrials.gov; March 27, 2020; NCT04340557.