Impact of a Rapid Molecular Test for Klebsiella pneumoniae Carbapenemase and Ceftazidime-Avibactam Use on Outcomes After Bacteremia Caused by Carbapenem-Resistant Enterobacterales.

BACKGROUND: Patients with bacteremia due to carbapenem-resistant Enterobacterales (CRE) experience delays until appropriate therapy and high mortality rates. Rapid molecular diagnostics for carbapenemases and new ß-lactam/ß-lactamase inhibitors may improve outcomes. METHODS: We conducted an observational study of patients with CRE bacteremia from 2016 to 2018 at 8 New York and New Jersey medical centers and assessed center-specific clinical microbiology practices. We compared time to receipt of active antimicrobial therapy and mortality between patients whose positive blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase (KPC) gene (blaKPC) and patients whose cultures did not undergo this test. CRE isolates underwent antimicrobial susceptibility testing by broth microdilution and carbapenemase profiling by whole-genome sequencing. We also assessed outcomes when ceftazidime-avibactam and polymyxins were used as targeted therapies. RESULTS: Of 137 patients with CRE bacteremia, 89 (65%) had a KPC-producing organism. Patients whose blood cultures underwent blaKPC PCR testing (n = 51) had shorter time until receipt of active therapy (median: 24 vs 50 hours; P = .009) compared with other patients (n = 86) and decreased 14-day (16% vs 37%; P = .007) and 30-day (24% vs 47%; P = .007) mortality. blaKPC PCR testing was associated with decreased 30-day mortality (adjusted odds ratio: .37; 95% CI: .16-.84) in an adjusted model. The 30-day mortality rate was 10% with ceftazidime-avibactam monotherapy and 31% with polymyxin monotherapy (P = .08). CONCLUSIONS: In a KPC-endemic area, blaKPC PCR testing of positive blood cultures was associated with decreased time until appropriate therapy and decreased mortality for CRE bacteremia, and ceftazidime-avibactam is a reasonable first-line therapy for these infections.

Racial/ethnic disparities on inflammation and response to methylprednisolone in severe COVID-19 pneumonia.

BACKGROUND: Racial/ethnic minorities are at higher risk for severe COVID-19. This may be related to social determinants that lead to chronic inflammatory states. The aims of the study were to determine if there are racial/ethnic disparities with inflammatory markers and association of methylprednisolone to in hospital survival. METHODS: This was a secondary analysis of a retrospective cohort study of patients ≥ 18 years of age and admitted for severe COVID-19 pneumonia between March and June 2020 in 13 Hospitals in New Jersey, United States. Patients who received other formulation of corticosteroids were not included. Area under the receiver operating characteristics curves were performed to test for discriminatory ability of each inflammatory makers. Univariate and multivariate Cox regression assessed the association of variables to in hospital survival. RESULTS: Propensity matched sample (n = 759) between no methylprednisolone (n = 380) and methylprednisolone (n = 379) had 338 Whites, 102 Blacks, 61 Asian/Indians, and 251 non-Black non-White Hispanics. Compared to CRP, area under receiving operating characteristic curve for d-dimer in Hispanics (0.742) was statistically different (DeLong Test P = 0.0041). Multivariate cox regression showed that different variables in Blacks [age ≥ 60 years (HR = 3.71, P = 0.0281), mechanical ventilation (HR = 5.07, P = 0.0281) and creatinine ≥ 1.5 mg/dL (HR = 3.61, P = 0.0007)], Whites [cancer (HR = 1.68, P = 0.0213), qSOFA score of 1 (HR = 1.81, P = 0.0213), qSOFA score of 2 (HR = 5.16, P < 0.0001), qSOFA score of 3 (HR = 11.81, P < 0.0001) and creatinine ≥ 1.5 mg/dL (HR = 2.16, P = 0.0006)], Hispanics [hypertension (HR = 2.52, P = 0.0007), cancer (HR = 2.99, P = 0.0244 and D-dimer ≥ 2 mcg/mL (HR = 2.22, P = 0.0077)], and Asian/Indians [ chronic kidney disease (HR = 6.36, P = 0.0031) and CRP > 20 mg/L (HR = 5.02, P = 0.0032)] were statistically significant for mortality. Low dose and high dose methylprednisolone were significantly associated with prolonged survival in Whites [low dose (HR = 0.37, P < 0.0001) and high dose (HR = 0.48, P < 0.0183)] and Asian/Indians [low dose (HR = 0.13, P = 0.0101) and high dose (HR = 0.15, P = 0.01)]. However, high dose was not associated with improved survival compared to low dose. Methylprednisolone was not associated with prolonged survival in Blacks and Hispanics. CONCLUSION: Racial/Ethnic disparities with inflammatory markers preclude the use of one marker as a predictor of survival. Methylprednisolone is associated with prolonged survival in Asian/Indians and Whites.

Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial.

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. CLINICAL TRIALS REGISTRATION: NCT04315298.

Methylprednisolone and 60 Days in Hospital Survival in Coronavirus Disease 2019 Pneumonia.

OBJECTIVES: To determine methylprednisolone's dose, duration, and administration from onset of symptoms and association with 60 days in hospital survival of coronavirus disease 2019 pneumonia. DESIGN: Cohort study. SETTING: Thirteen hospitals in New Jersey, United States during March to June 2020. PATIENTS: Seven-hundred fifty-nine hospitalized coronavirus disease 2019 patients. INTERVENTIONS: We performed a propensity matched cohort study between patients who received methylprednisolone and no methylprednisolone. Patients in the methylprednisolone group were further differentiated into dose (high dose and low dose), duration, and administration from onset of symptoms. MEASUREMENTS AND MAIN RESULTS: In the propensity matched sample, 99 out of 380 (26%) in no methylprednisolone, 69 out of 215 (31.9%) in low-dose methylprednisolone, and 74 out of 164 (55.2%) high-dose methylprednisolone expired. Overall median survival for no methylprednisolone (25.0 d), low-dose methylprednisolone (39.0 d), high-dose methylprednisolone (20.0 d), less than or equal to 7 days duration (19.0 d), 7-14 days duration (30.0 d), greater than 14 days duration (44.0 d), onset of symptoms less than or equal to 7 days (20.0 d), and onset of symptoms 7-14 days (27.0 d) were statistically significant (log-rank p ≤ 0.001). Multivariate Cox regression showed nursing home residents, coronary artery disease, and invasive mechanical ventilation were independently associated with mortality. Methylprednisolone was associated with reduced mortality compared with no methylprednisolone (hazard ratio, 0.40; 95% CI, 0.27-0.59; p < 0.001) but no added benefit with high dose. Low-dose methylprednisolone for 7-14 days was associated with reduced mortality compared with less than or equal to 7 days (hazard ratio, 0.45; 95% CI, 0.22-0.91; p = 0.0273), and no additional benefit if greater than 14 days (hazard ratio, 1.27; 95% CI, 0.60-2.69; p = 0.5434). Combination therapy with tocilizumab was associated with reduced mortality over monotherapy (p < 0.0116). CONCLUSIONS: Low-dose methylprednisolone was associated with reduced mortality if given greater than 7 days from onset of symptoms, and no additional benefit greater than 14 days. High dose was associated with higher mortality.

Multicenter Clinical and Molecular Epidemiological Analysis of Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States.

Although the New York/New Jersey (NY/NJ) area is an epicenter for carbapenem-resistant Enterobacteriaceae (CRE), there are few multicenter studies of CRE from this region. We characterized patients with CRE bacteremia in 2013 at eight NY/NJ medical centers and determined the prevalence of carbapenem resistance among Enterobacteriaceae bloodstream isolates and CRE resistance mechanisms, genetic backgrounds, capsular types (cps), and antimicrobial susceptibilities. Of 121 patients with CRE bacteremia, 50% had cancer or had undergone transplantation. The prevalences of carbapenem resistance among Klebsiella pneumoniae, Enterobacter spp., and Escherichia coli bacteremias were 9.7%, 2.2%, and 0.1%, respectively. Ninety percent of CRE were K. pneumoniae and 92% produced K. pneumoniae carbapenemase (KPC-3, 48%; KPC-2, 44%). Two CRE produced NDM-1 and OXA-48 carbapenemases. Sequence type 258 (ST258) predominated among KPC-producing K. pneumoniae (KPC-Kp). The wzi154 allele, corresponding to cps-2, was present in 93% of KPC-3-Kp, whereas KPC-2-Kp had greater cps diversity. Ninety-nine percent of CRE were ceftazidime-avibactam (CAZ-AVI)-susceptible, although 42% of KPC-3-Kp had an CAZ-AVI MIC of ≥4/4 µg/ml. There was a median of 47 h from bacteremia onset until active antimicrobial therapy, 38% of patients had septic shock, and 49% died within 30 days. KPC-3-Kp bacteremia (adjusted odds ratio [aOR], 2.58; P = 0.045), cancer (aOR, 3.61, P = 0.01), and bacteremia onset in the intensive care unit (aOR, 3.79; P = 0.03) were independently associated with mortality. Active empirical therapy and combination therapy were not associated with survival. Despite a decade of experience with CRE, patients with CRE bacteremia have protracted delays in appropriate therapies and high mortality rates, highlighting the need for rapid diagnostics and evaluation of new therapeutics.

Echinacea purpurea for prevention of experimental rhinovirus colds.

A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the ability of Echinacea purpurea to prevent infection with rhinovirus type 39 (RV-39). Forty-eight previously healthy adults received echinacea or placebo, 2.5 mL 3 times per day, for 7 days before and 7 days after intranasal inoculation with RV-39. Symptoms were assessed to evaluate clinical illness. Viral culture and serologic studies were performed to evaluate the presence of rhinovirus infection. A total of 92% of echinacea recipients and 95% of placebo recipients were infected. Colds developed in 58% of echinacea recipients and 82% of placebo recipients (P=.114, by Fisher's exact test). Administration of echinacea before and after exposure to rhinovirus did not decrease the rate of infection; however, because of the small sample size, statistical hypothesis testing had relatively poor power to detect statistically significant differences in the frequency and severity of illness.