Early Outpatient Treatment for Covid-19 with Convalescent Plasma.

BACKGROUND: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain. METHODS: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion. RESULTS: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized. CONCLUSIONS: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

Symptom Duration and Resolution With Early Outpatient Treatment of Convalescent Plasma for Coronavirus Disease 2019: A Randomized Trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) reduces hospitalizations among outpatients treated early after symptom onset. It is unknown whether CCP reduces time to symptom resolution among outpatients. METHODS: We evaluated symptom resolution at day 14 by trial arm using an adjusted subdistribution hazard model, with hospitalization as a competing risk. We also assessed the prevalence of symptom clusters at day 14 between treatments. Clusters were defined based on biologic clustering, impact on ability to work, and an algorithm. RESULTS: Among 1070 outpatients followed up after transfusion, 381 of 538 (70.8%) receiving CCP and 381 of 532 (71.6%) receiving control plasma were still symptomatic (P = .78) at day 14. Associations between CCP and symptom resolution by day 14 did not differ significantly from those in controls after adjustment for baseline characteristics (adjusted subdistribution hazard ratio, 0.99; P = .62). The most common cluster consisted of cough, fatigue, shortness of breath, and headache and was found in 308 (57.2%) and 325 (61.1%) of CCP and control plasma recipients, respectively (P = .16). CONCLUSIONS: In this trial of outpatients with early COVID-19, CCP was not associated with faster resolution of symptoms compared with control. Overall, there were no differences by treatment in the prevalence of each symptom or symptom clusters at day 14. CLINICAL TRIALS REGISTRATION: NCT04373460.

Infectious Diseases Consultation Associated With Reduced Mortality in Gram-Negative Bacteremia.

Gram-negative bacteremia (GN-BSI) can cause significant morbidity and mortality, but the benefit of infectious diseases consultation (IDC) is not well defined. A 24-site observational cohort study of unique hospitalized patients with 4861 GN-BSI episodes demonstrated a 40% decreased risk of 30-day mortality in patients with IDC compared to those without IDC.

Excellence in Antibiotic Stewardship: A mixed methods study comparing High, Medium, and Low Performing Hospitals.

BACKGROUND: Despite antibiotic stewardship programs existing in most acute care hospitals, there continues to be variation in appropriate antibiotic use. While existing research examines individual prescriber behavior, contextual reasons for variation are poorly understood. METHODS: We conducted an explanatory, sequential mixed methods study of a purposeful sample of 7 hospitals with varying discharge antibiotic overuse. For each hospital, we conducted surveys, document analysis, and semi-structured interviews with antibiotic stewardship and clinical stakeholders. Data were analyzed separately and mixed during the interpretation phase, where each hospital was examined as a case, with findings organized across cases using a strengths, weaknesses, opportunities, and threats framework to identify factors accounting for differences in antibiotic overuse across hospitals. RESULTS: Surveys included 85 respondents. Interviews included 90 respondents (31 hospitalists, 33 clinical pharmacists, 14 stewardship leaders, 12 hospital leaders). On surveys, clinical pharmacists at hospitals with lower antibiotic overuse were more likely to report feeling: respected by hospitalist colleagues (p=0.001), considered valuable team members (p=0.001), comfortable recommending antibiotic changes (p=0.02). Based on mixed-methods analysis, hospitals with low antibiotic overuse had four distinguishing characteristics: a) robust knowledge of and access to antibiotic stewardship guidance, b) high quality clinical pharmacist-physician relationships, c) tools and infrastructure to support stewardship, and d) highly engaged Infectious Diseases physicians who advocated stewardship principles. CONCLUSION: This mixed-method study demonstrates the importance of organizational context for high performance in stewardship and suggests improving antimicrobial stewardship requires attention to knowledge, interactions, and relationships between clinical teams and infrastructure that supports stewardship and team interactions.

Transfusion reactions associated with COVID-19 convalescent plasma in outpatient clinical trials.

BACKGROUND: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials. STUDY DESIGN AND METHODS: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders. RESULTS: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications. DISCUSSION: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19.

Urgent, Comprehensive Federal Action Needed To Stem Mortality and Medicare Costs Associated With Antimicrobial Resistance.

This paper is a call to action for the policies necessary to reduce the burden of antimicrobial resistance, including federal investments in antibiotic stewardship, antibiotic innovation, surveillance, research, diagnostics, infection prevention, the infectious diseases workforce, and global coordination.

Antibiotic Overuse and Stewardship at Hospital Discharge: The Reducing Overuse of Antibiotics at Discharge Home Framework.

Though opportunities exist to improve antibiotic prescribing across the care spectrum, discharge from acute hospitalization is an increasingly recognized source of antibiotic overuse. Antimicrobials are prescribed to more than 1 in 8 patients at hospital discharge; approximately half of which could be improved. Key targets for antibiotic stewardship at discharge include unnecessary antibiotics, excess duration, avoidable fluoroquinolones, and improving (or avoiding) intravenous antibiotic therapy. Barriers to discharge antibiotic stewardship include the perceived "high stakes" of care transitions during which patients move from intense to infrequent observation, difficulties in antibiotic measurement to guide improvement at discharge, and poor communication across silos, particularly with skilled nursing facilities. In this review, we discuss what is currently known about antibiotic overuse at hospital discharge, key barriers, and targets for improving antibiotic prescribing at discharge and we introduce an evidence-based framework, the Reducing Overuse of Antibiotics at Discharge Home Framework, for conducting discharge antibiotic stewardship.

Optimal Urine Culture Diagnostic Stewardship Practice-Results from an Expert Modified-Delphi Procedure.

BACKGROUND: Urine cultures are nonspecific and often lead to misdiagnosis of urinary tract infection and unnecessary antibiotics. Diagnostic stewardship is a set of procedures that modifies test ordering, processing, and reporting in order to optimize diagnosis and downstream treatment. In this study, we aimed to develop expert guidance on best practices for urine culture diagnostic stewardship. METHODS: A RAND-modified Delphi approach with a multidisciplinary expert panel was used to ascertain diagnostic stewardship best practices. Clinical questions to guide recommendations were grouped into three thematic areas (ordering, processing, reporting) in practice settings of emergency department, inpatient, ambulatory, and long-term care. Fifteen experts ranked recommendations on a 9-point Likert scale. Recommendations on which the panel did not reach agreement were discussed during a virtual meeting, then a second round of ranking by email was completed. After secondary review of results and panel discussion, a series of guidance statements was developed. RESULTS: One hundred and sixty-five questions were reviewed. The panel reaching agreement on 104, leading to 18 overarching guidance statements. The following strategies were recommended to optimize ordering urine cultures: requiring documentation of symptoms, sending alerts to discourage ordering in the absence of symptoms, and cancelling repeat cultures. For urine culture processing, conditional urine cultures and urine white blood cell count as criteria were supported. For urine culture reporting, appropriate practices included nudges to discourage treatment under specific conditions and selective reporting of antibiotics to guide therapy decisions. CONCLUSIONS: These 18 guidance statements can optimize use of urine cultures for better patient outcomes.

Epidemiology, Disposition, and Treatment of Ambulatory Veterans With Skin and Soft Tissue Infections.

BACKGROUND: Most skin and soft tissue infections (SSTIs) are managed in the outpatient setting, but data are lacking on treatment patterns outside the emergency department (ED). Available data suggest that there is poor adherence to SSTI treatment guidelines. METHODS: We conducted a retrospective cohort study of Veterans diagnosed with SSTIs in the ED or outpatient clinics from 1 January 2005 through 30 June 2018. The incidence of SSTIs over time was modeled using Poisson regression using robust standard errors. Antibiotic selection and incision and drainage (I&D) were described and compared between ambulatory settings. Anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotic use was compared to SSTI treatment guidelines. RESULTS: There were 1 740 992 incident SSTIs in 1 156 725 patients during the study period. The incidence of SSTIs significantly decreased from 4.58 per 1000 patient-years in 2005 to 3.27 per 1000 patient-years in 2018 (P < .001). There were lower rates of ß-lactam prescribing (32.5% vs 51.7%) in the ED compared to primary care (PC), and higher rates of anti-MRSA therapy (51.4% vs 35.1%) in the ED compared to PC. The I&D rate in the ED was 8.1% compared to 2.6% in PC. Antibiotic regimens without MRSA activity were prescribed in 24.9% of purulent SSTIs. Anti-MRSA antibiotics were prescribed in 40.1% of nonpurulent SSTIs. CONCLUSIONS: We found a decrease in the incidence of SSTIs in the outpatient setting over time. Treatment of SSTIs varied depending on the presenting ambulatory location. There is poor adherence to guidelines in regard to use of anti-MRSA therapies. Further study is needed to understand the impact of guideline nonadherence on patient outcomes.

Impact of Implementation of the Core Elements of Outpatient Antibiotic Stewardship Within Veterans Health Administration Emergency Departments and Primary Care Clinics on Antibiotic Prescribing and Patient Outcomes.

BACKGROUND: The Core Elements of Outpatient Antibiotic Stewardship provide a framework to improve antibiotic use. We report the impact of core elements implementation within Veterans Health Administration sites. METHODS: In this quasiexperimental controlled study, effects of an intervention targeting antibiotic prescription for uncomplicated acute respiratory tract infections (ARIs) were assessed. Outcomes included per-visit antibiotic prescribing, treatment appropriateness, ARI revisits, hospitalization, and ARI diagnostic changes over a 3-year pre-implementation period and 1-year post-implementation period. Logistic regression adjusted for covariates (odds ratio [OR], 95% confidence interval [CI]) and a difference-in-differences analysis compared outcomes between intervention and control sites. RESULTS: From 2014-2019, there were 16 712 and 51 275 patient visits within 10 intervention and 40 control sites, respectively. Antibiotic prescribing rates pre- and post-implementation within intervention sites were 59.7% and 41.5%, compared to 73.5% and 67.2% within control sites, respectively (difference-in-differences, P < .001). Intervention site pre- and post-implementation OR to receive appropriate therapy increased (OR, 1.67; 95% CI, 1.31-2.14), which remained unchanged within control sites (OR,1.04; 95% CI, .91-1.19). ARI-related return visits post-implementation (-1.3% vs -2.0%; difference-in-differences P = .76) were not different, but all-cause hospitalization was lower within intervention sites (-0.5% vs -0.2%; difference-in-differences P = .02). The OR to diagnose non-specific ARI compared with non-ARI diagnoses increased post-implementation forintervention (OR, 1.27; 95% CI, 1.21 -1.34) but not control (OR, 0.97; 95% CI, .94-1.01) sites. CONCLUSIONS: Implementation of the core elements was associated with reduced antibiotic prescribing for RIs and a reduction in hospitalizations. Diagnostic coding changes were observed.

Validation of a Community-Acquired Pneumonia Score To Improve Empiric Antibiotic Selection at an Academic Medical Center.

The 2019 American Thoracic Society and the Infectious Diseases Society of America community-acquired pneumonia (CAP) guidelines recommend that drug-resistant pathogens (DRP) be empirically covered if locally validated risk factors are present. This retrospective case-control validation study evaluated the performance of the drug resistance in pneumonia (DRIP) clinical prediction score. Two hundred seventeen adult patients with ICD-10 (https://www.who.int/classifications/classification-of-diseases) pneumonia diagnosis, positive confirmed microbiologic data, and clinical signs and symptoms were included. A DRIP score of ≥4 was used to assess model performance. Logistic regression was used to select for significant predictors and create a modified DRIP score, which was evaluated to define clinical application. The DRIP score predicted pneumonia due to a DRP with a sensitivity of 67% and specificity of 73%. The area under the receiver operating characteristic (AUROC) curve was 0.76 (95% confidence interval [CI], 0.69 to 0.82). From regression analysis, prior infection with a DRP and antibiotics in the last 60 days, yielding scores of 2 points and 1 point, respectively, remained local risk factors in predicting drug-resistant pneumonia. Sensitivity (47%) and specificity (94%) were maximized at a threshold of ≥2 in the modified DRIP model. Therefore, prior infection with a DRP remained the only clinically relevant predictor for drug-resistant pneumonia. The original DRIP score demonstrated a decreased performance in our patient population and behaved similarly to other clinical prediction models. Empiric CAP therapy without anti-methicillin-resistant Staphylococcus aureus and antipseudomonal coverage should be considered for noncritically ill patients without a drug resistant pathogen infection in the past year. Our data support the necessity of local validation to authenticate clinical risk predictors for drug-resistant pneumonia.

Disproportionality Analysis of Safety with Nafcillin and Oxacillin with the FDA Adverse Event Reporting System (FAERS).

Antistaphylococcal penicillins such as nafcillin and oxacillin are among the first choices of treatment for severe invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections, although there has been limited safety evaluations between individual agents. Using the FDA Adverse Event Reports System (FAERS), oxacillin was observed to have a lower proportion of reports of acute renal failure (reporting odds ratio [ROR], 5.3 [95% confidence interval {CI}, 3.1 to 9.3] versus 21.3 [95% CI, 15.8 to 28.6], respectively) and hypokalemia (ROR, 0.7 [95% CI, 0.1 to 4.8] versus 11.4 [95% CI, 7.1 to 18.3], respectively) than nafcillin.

Essential Resources and Strategies for Antibiotic Stewardship Programs in the Acute Care Setting.

Background: Antibiotic stewardship programs improve clinical outcomes and patient safety and help combat antibiotic resistance. Specific guidance on resources needed to structure stewardship programs is lacking. This manuscript describes results of a survey of US stewardship programs and resultant recommendations regarding potential staffing structures in the acute care setting. Methods: A cross-sectional survey of members of 3 infectious diseases subspecialty societies actively involved in antibiotic stewardship was conducted. Survey responses were analyzed with descriptive statistics. Logistic regression models were used to investigate the relationship between stewardship program staffing levels and self-reported effectiveness and to determine which strategies mediate effectiveness. Results: Two-hundred forty-four respondents from a variety of acute care settings completed the survey. Prior authorization for select antibiotics, antibiotic reviews with prospective audit and feedback, and guideline development were common strategies. Eighty-five percent of surveyed programs demonstrated effectiveness in at least 1 outcome in the prior 2 years. Each 0.50 increase in pharmacist and physician full-time equivalent (FTE) support predicted a 1.48-fold increase in the odds of demonstrating effectiveness. The effect was mediated by the ability to perform prospective audit and feedback. Most programs noted significant barriers to success. Conclusions: Based on our survey's results, we propose an FTE-to-bed ratio that can be used as a starting point to guide discussions regarding necessary resources for antibiotic stewardship programs with executive leadership. Prospective audit and feedback should be the cornerstone of stewardship programs, and both physician leadership and pharmacists with expertise in stewardship are crucial for success.

Comparison of the Drug-Drug Interaction Potential of Daptomycin in Combination with Rifampin in Healthy Adult Volunteers.

We evaluated the effects of rifampin coadministration and MDR1 single nucleotide polymorphisms on the disposition of daptomycin in twelve healthy adults. There were no significant changes from baseline in the clearance (0.53 versus 0.55 liters/h, P = 1.00), volume of distribution (7.0 versus 7.2 liter, P = 0.62), or half-life (9.7 versus 9.6 h, P = 0.89) of daptomycin after exposure to rifampin. The tested MDR1 polymorphisms were not associated with significant differences in daptomycin disposition.

Candida auris: an Emerging Fungal Pathogen.

Candida auris has emerged globally as a multidrug-resistant health care-associated fungal pathogen. Recent reports highlight ongoing challenges due to organism misidentification, high rates of antifungal drug resistance, and significant patient mortality. The predilection for transmission within and between health care facilities possibly promoted by virulence factors that facilitate skin colonization and environmental persistence is unique among Candida species. This minireview details the global emergence of C. auris and discusses issues relevant to clinical microbiology laboratories, hospital infection control, and antimicrobial stewardship efforts.

A Chlorhexidine Solution Reduces Aerobic Organism Growth in Operative Splash Basins in a Randomized Controlled Trial.

BACKGROUND: Despite recommendations against the use of splash basins, due to the potential of bacterial contamination, our observation has been that they continue to be used in operating theaters. In hopes of decontaminating the splash basin, we sought to determine if the addition of chlorhexidine gluconate (CHG) would eliminate aerobic bacterial growth within the splash basin. METHODS: After Institutional Review Board approval, we began enrollment in a randomized controlled trial comparing 2 splash basin solutions. Splash basins (n = 111) were randomized to either the standard of care (control) solution of sterile water or the experimental solution containing 0.05% CHG. One 20 mL aliquot was taken from the basin at the end of the surgical case and delivered to an independent laboratory. Samples were plated on tryptic soy agar (medium) and incubated at 30°C-35°C to encourage growth. After 48-72 hours, the agar plates were examined for growth and a standard plate count of aerobic cultures was performed. RESULTS: The sterile water group was found to have bacterial growth in 9% of samples compared to no growth in the CHG group (P = .045). The organisms included Micrococcus luteus, Staphylococcus hominis, Gram-variable coccobacilli, and unidentifiable Gram-positive rods. CONCLUSION: Given the safety and efficacy of a concentration of 0.05% CHG in reducing the bacterial contamination in the operative splash basin, it would seem that if the practice of using a splash basin in the operating theater is to be continued, the addition of an antiseptic solution such as that studied here should be considered.

Management of Bacteriuria in Veterans Affairs Hospitals.

BACKGROUND: Bacteriuria contributes to antibiotic overuse through treatment of asymptomatic bacteriuria (ASB) and long durations of therapy for symptomatic urinary tract infections (UTIs), yet large-scale evaluations of bacteriuria management among inpatients are lacking. METHODS: Inpatients with bacteriuria were classified as asymptomatic or symptomatic based on established criteria applied to data collected by manual chart review. We examined frequency of treatment of ASB, factors associated with treatment of ASB, durations of therapy, and frequency of complications including Clostridium difficile infection, readmission, and all-cause mortality within 28 days of discharge. RESULTS: Among 2225 episodes of bacteriuria, 64% were classified as ASB. After excluding patients with non-UTI indications for antibiotics, 72% of patients with ASB received antibiotics. When evaluating only patients not meeting SIRS criteria, 68% of patients with ASB received antibiotics. The mean (±SD) days of antibiotic therapy for ASB, cystitis, CA-UTI and pyelonephritis were 10.0 (4.5), 11.4 (4.7), 12.0 (6.1), and 13.6 (5.3), respectively. In sum, 14% of patients with ASB were treated for greater than 14 days, and fluoroquinolones were the most commonly used empiric antibiotic for ASB [245/691 (35%)]. Complications were rare but more common among patients with ASB treated with antibiotics. CONCLUSIONS: The majority of bacteriuria among inpatient veterans is due to ASB with high rates of treatment of ASB and prolonged durations of therapy for ASB and symptomatic UTIs.

Measuring Appropriate Antimicrobial Use: Attempts at Opening the Black Box.

Indiscriminate antimicrobial use has plagued medicine since antibiotics were first introduced into clinical practice >70 years ago. Infectious diseases physicians and public health officials have advocated for preservation of these life-saving drugs for many years. With rising burden of antimicrobial-resistant organisms and Clostridium difficile infections, halting unnecessary antimicrobial use has become one of the largest public health concerns of our time. Inappropriate antimicrobial use has been quantified in various settings using numerous definitions; however, no established reference standard exists. With mounting national efforts to improve antimicrobial use, a consensus definition and standard method of measuring appropriate antimicrobial use is imperative. We review existing literature on systematic approaches to define and measure appropriate antimicrobial use, and describe a collaborative effort at developing standardized audit tools for assessing the quality of antimicrobial prescribing.