Early Initiation of Ceftaroline-Based Combination Therapy for Methicillin-resistant Staphylococcus aureus Bacteremia.

Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B. Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 hours of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression. Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 hours. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups. Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy.

Building the future of ID: A call to action for quality improvement research and measurement.

Quality is central to value-based care and measurement is essential for assessing performance and understanding improvement over time. Both value-based care and methods for quality measurement are evolving. Infectious Diseases has been less engaged than other specialties in quality measure development, and Infectious Diseases providers must seize the opportunity to engage with quality measure development and research. Antimicrobial stewardship programs are an ideal starting point for Infectious Diseases-related quality measure development; antimicrobial stewardship program interventions and best practices are Infectious Diseases-specific, measurable, and impactful, yet grossly undercompensated. Herein, we provide a scheme for prioritizing research focused on development of Infectious Diseases-specific quality measures. Maturation of quality measurement research in Infectious Diseases, beginning with an initial focus on stewardship-related conditions then expanding to non-stewardship topics, will allow Infectious Diseases to take control of its future in value-based care, and promote the growth of Infectious Diseases through greater recognition of its value.

First-Dose Antimicrobial Infusion Reactions in Patients Enrolled in Outpatient Parenteral Antimicrobial Therapy Services.

After receiving a monitored first-dose antimicrobial infusion at an infusion center, 6 of 93 (6%) patients enrolled in outpatient parenteral antimicrobial therapy services experienced an immediate reaction, none of which were consistent with immunoglobulin E-mediated reactions. These findings suggest it would be reasonable to forgo monitoring for most patients receiving first-dose intravenous antimicrobials outpatient.

Phagocytosis via complement receptor 3 enables microbes to evade killing by neutrophils.

CR3 (CD11b/CD18; αmß2 integrin) is a conserved phagocytic receptor. The active conformation of CR3 binds the iC3b fragment of complement C3 as well as many host and microbial ligands, leading to actin-dependent phagocytosis. There are conflicting reports about how CR3 engagement affects the fate of phagocytosed substrates. Using imaging flow cytometry, we confirmed that binding and internalization of iC3b-opsonized polystyrene beads by primary human neutrophils was CR3-dependent. iC3b-opsonized beads did not stimulate neutrophil reactive oxygen species, and most beads were found in primary granule-negative phagosomes. Similarly, Neisseria gonorrhoeae that does not express phase-variable Opa proteins suppresses neutrophil reactive oxygen species and delays phagolysosome formation. Here, binding and internalization of Opa-deleted (Δopa) N. gonorrhoeae by adherent human neutrophils was inhibited using blocking antibodies against CR3 and by adding neutrophil inhibitory factor, which targets the CD11b I-domain. No detectable C3 was deposited on N. gonorrhoeae in the presence of neutrophils alone. Conversely, overexpressing CD11b in HL-60 promyelocytes enhanced Δopa N. gonorrhoeae phagocytosis, which required the CD11b I-domain. Phagocytosis of N. gonorrhoeae was also inhibited in mouse neutrophils that were CD11b-deficient or treated with anti-CD11b. Phorbol ester treatment upregulated surface CR3 on neutrophils in suspension, enabling CR3-dependent phagocytosis of Δopa N. gonorrhoeae. Neutrophils exposed to Δopa N. gonorrhoeae had limited phosphorylation of Erk1/2, p38, and JNK. Neutrophil phagocytosis of unopsonized Mycobacterium smegmatis, which also resides in immature phagosomes, was CR3-dependent and did not elicit reactive oxygen species. We suggest that CR3-mediated phagocytosis is a silent mode of entry into neutrophils, which is appropriated by diverse pathogens to subvert phagocytic killing.

Risk Factors for Severe COVID-19 Among Health Care Workers.

OBJECTIVE: Evaluate potential risk factors for severe coronavirus disease 2019 (COVID-19) among health care workers (HCWs) at the University of Virginia Medical Center in Charlottesville, Virginia. METHODS: We conducted a retrospective manual chart review of data from HCWs who were diagnosed with COVID-19 from March 2020 to March 2021. Using data from patient medical histories, we ascertained risk factors for COVID-19-related emergency department encounter, hospitalization, or death. RESULTS: We had 634 patients in total, and 9.8% had a severe COVID-19-related outcome. A history of deep vein thrombosis/pulmonary embolism/stroke (odds ratio, 19.6; 95% confidence interval, 5.11 to 94.7), as well as asthma, chronic lung disease, diabetes, or current immunocompromised status, was associated with increased adjusted odds of COVID-19-related emergency department encounter/hospitalization/death. CONCLUSIONS: A preexisting history of deep vein thrombosis/pulmonary embolism/stroke is a novel risk factor for poor COVID-19 outcomes among a cohort of HCWs.

Influence of critically appraising exemption requests from healthcare personnel along a spectrum of influenza vaccine hesitancy.

OBJECTIVES: This study was performed to assess whether an intervention for critically appraising influenza vaccine exemption requests from healthcare personnel (HCP) affected (1) the overall rate of influenza vaccine exemption within a healthcare institution and/or (2) the rates of postintervention vaccine acceptance among those who inconsistently request exemption from annual vaccination and those who consistently request exemption from vaccination. DESIGN: Retrospective, before-and-after intervention study. SETTING: We conducted the study at a single academic medical center. PARTICIPANTS: This study included 29,663 HCP. METHODS: Between 2010 and 2019, HCP were permitted to request an exemption from influenza vaccination without critical appraisal of exemption requests. After January 2019, medical center policy required critical appraisal of exemption requests. Of those employed 3 or more years who requested an exemption at least once during the preintervention period (n = 1,177), those with unchanging exemption reasons annually were termed "consistent exempters." Those who changed reasons or accepted vaccination n ≥ 1 times were termed "inconsistent exempters." RESULTS: The overall exemption rate from influenza vaccine decreased from 3.8% to 1.2% (P < .001; N = 29,663) after the intervention. Of those requesting exemption at least once before the intervention, 329 (28.0%) of 1,177 were consistent exempters and 878 (72.0%) were inconsistent exempters. Of inconsistent exempters employed after the intervention, 442 (88.9%) of 497 accepted vaccine postintervention compared with 118 (59.6%) of 198 consistent exempters (P < .001). Of all exempters who changed from exemption to acceptance after the intervention, 442 (78.9%) of 560 were inconsistent exempters. CONCLUSIONS: Critical appraisal of HCP exemption requests promotes influenza vaccine acceptance, and acceptance by inconsistent exempters drives the effect of the intervention. Analysis of changes in annual exemption requests represents a novel objective method for describing those on the spectrum of vaccine hesitancy.

Tolerability of Cefazolin in Nafcillin-Intolerant Patients for the Treatment of Methicillin-Susceptible Staphylococcus aureus Infections.

BACKGROUND: Non-immunoglobulin E (IgE)-mediated hypersensitivity reactions (HSRs) to nafcillin are commonly reported, but scarce data are available to guide appropriate antibiotic change following these reactions. Although cefazolin is an attractive therapeutic alternative in methicillin-susceptible Staphylococcus aureus (MSSA) infections when patients experience an HSR to nafcillin, more data are needed to evaluate the tolerability of cefazolin after switching from nafcillin. The purpose of this study was to describe the tolerability of cefazolin in patients who develop a suspected non-IgE-mediated HSR to nafcillin. METHODS: This was a retrospective, descriptive case series of patients who received nafcillin for an MSSA infection, experienced a suspected non-IgE-mediated HSR, and were switched to cefazolin between October 2015 and November 2019 at a single academic medical center. The primary objective was to identify the percentage of patients who completed cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin. RESULTS: There were 80 patients with 87 prespecified non-IgE-mediated HSRs during the study period. Seventy-one (89%) patients completed cefazolin, with 53 (75%) of these patients completing at least 2 weeks of therapy. One patient was ultimately switched from cefazolin to daptomycin due to concern for treatment failure. Eight patients (10%) did not tolerate cefazolin after switching from nafcillin. Of these, 3 patients experienced an unrelated HSR, whereas 5 patients experienced the same non-IgE-mediated HSR that was attributed to nafcillin and discontinued cefazolin within 7 days. The most common HSR cited was immune-mediated nephritis; however, the majority were clinically presumed but did not meet objective diagnostic criteria. CONCLUSIONS: Treatment with cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin appears to be safe, even for patients requiring a prolonged duration of cefazolin.

Infectious Disease Providers' Knowledge of and Engagement in Quality Improvement.

Background: Although engagement of infectious disease physicians has been demonstrated to improve clinical outcomes in a variety of disease states, the extent of infectious disease (ID) physician engagement in quality improvement (QI) or their knowledge of QI has not been assessed. Methods: A 12-question, web-based survey was distributed to members of the Infectious Diseases Society of America (IDSA) between August and October 2019 to assess knowledge of and engagement in QI. The survey link was sent to IDSA members who self-identified patient care as their primary professional activity. Results: Responses were received from 200 individuals (5.4% response rate, which is just below the standard IDSA survey response rate of 6%), consisting of 175 adult infectious disease physicians (IDPs). Most respondents were employed in a hospital or clinic (41%), private or group practice (25%), or university/medical center (24%). Fifty-eight percent of respondents currently participate in QI projects, while 38% serve on QI oversight committees. Among respondents, 27% reported not being engaged in QI. Infection prevention/hospital epidemiology (77%), stewardship (72%), and antimicrobial resistance (56%) were the most commonly reported measure types. Respondents reported barriers that limited participation in QI, including cost (61%), lack of time (56%), lack of data collection resources (48%), and lack of an ID-specific registry (46%). IDPs report significant interest in additional training in QI and new quality measures. Conclusions: Although IDPs participate in QI, there are gaps in QI knowledge and measurement systems. The low response rate of our survey also suggests a lack of engagement in QI among IDPs. Closing these gaps will benefit ID in a value-driven health care economy.

In Vivo Gene Essentiality and Metabolism in Bordetella pertussis.

Bordetella pertussis is the causative agent of whooping cough, a serious respiratory illness affecting children and adults, associated with prolonged cough and potential mortality. Whooping cough has reemerged in recent years, emphasizing a need for increased knowledge of basic mechanisms of B. pertussis growth and pathogenicity. While previous studies have provided insight into in vitro gene essentiality of this organism, very little is known about in vivo gene essentiality, a critical gap in knowledge, since B. pertussis has no previously identified environmental reservoir and is isolated from human respiratory tract samples. We hypothesize that the metabolic capabilities of B. pertussis are especially tailored to the respiratory tract and that many of the genes involved in B. pertussis metabolism would be required to establish infection in vivo In this study, we generated a diverse library of transposon mutants and then used it to probe gene essentiality in vivo in a murine model of infection. Using the CON-ARTIST pipeline, 117 genes were identified as conditionally essential at 1 day postinfection, and 169 genes were identified as conditionally essential at 3 days postinfection. Most of the identified genes were associated with metabolism, and we utilized two existing genome-scale metabolic network reconstructions to probe the effects of individual essential genes on biomass synthesis. This analysis suggested a critical role for glucose metabolism and lipooligosaccharide biosynthesis in vivo This is the first genome-wide evaluation of in vivo gene essentiality in B. pertussis and provides tools for future exploration.IMPORTANCE Our study describes the first in vivo transposon sequencing (Tn-seq) analysis of B. pertussis and identifies genes predicted to be essential for in vivo growth in a murine model of intranasal infection, generating key resources for future investigations into B. pertussis pathogenesis and vaccine design.

Analysis of the In Vivo Transcriptome of Bordetella pertussis during Infection of Mice.

Bordetella pertussis causes the disease whooping cough through coordinated control of virulence factors by the Bordetella virulence gene system. Microarrays and, more recently, RNA sequencing (RNA-seq) have been used to describe in vitro gene expression profiles of B. pertussis and other pathogens. In previous studies, we have analyzed the in vitro gene expression profiles of B. pertussis, and we hypothesize that the infection transcriptome profile in vivo is significantly different from that under laboratory growth conditions. To study the infection transcriptome of B. pertussis, we developed a simple filtration technique for isolation of bacteria from infected lungs. The work flow involves filtering the bacteria out of the lung homogenate using a 5-µm-pore-size syringe filter. The captured bacteria are then lysed to isolate RNA for Illumina library preparation and RNA-seq analysis. Upon comparing the in vitro and in vivo gene expression profiles, we identified 351 and 255 genes as activated and repressed, respectively, during murine lung infection. As expected, numerous genes associated with virulent-phase growth were activated in the murine host, including pertussis toxin (PT), the PT secretion apparatus, and the type III secretion system. A significant number of genes encoding iron acquisition and heme uptake proteins were highly expressed during infection, supporting iron acquisition as critical for B. pertussis survival in vivo Numerous metabolic genes were repressed during infection. Overall, these data shed light on the gene expression profile of B. pertussis during infection, and this method will facilitate efforts to understand how this pathogen causes infection.IMPORTANCEIn vitro growth conditions for bacteria do not fully recapitulate the host environment. RNA sequencing transcriptome analysis allows for the characterization of the infection gene expression profiles of pathogens in complex environments. Isolation of the pathogen from infected tissues is critical because of the large amounts of host RNA present in crude lysates of infected organs. A filtration method was developed that enabled enrichment of the pathogen RNA for RNA-seq analysis. The resulting data describe the "infection transcriptome" of B. pertussis in the murine lung. This strategy can be utilized for pathogens in other hosts and, thus, expand our knowledge of what bacteria express during infection.

How Do You Measure Up: Quality Measurement for Improving Patient Care and Establishing the Value of Infectious Diseases Specialists.

The shift from volume-based to value-based reimbursement has created a need for quantifying clinical performance of infectious diseases (ID) physicians. Nationally recognized ID specialty-specific quality measures will allow stakeholders, such as patients and payers, to determine the value of care provided by ID physicians and will promote clinical quality improvement. Few ID-specific measures have been developed; herein, we provide an overview of the importance of quality measurement for ID, discuss issues in quality measurement specific to ID, and describe standards by which candidate quality measures can be evaluated. If ID specialists recognize the need for quality measurement, then ID specialists can direct ID-related quality improvement, quantify the impact of ID physicians on patient outcomes, compare their performance to that of peers, and convey to stakeholders the value of the specialty.

The effect of rapid diagnostic testing with Infectious Diseases fellow consultative intervention on the management of enterococcal bloodstream infection.

BACKGROUND: Rapid diagnostics for enterococcal bloodstream infections (E-BSIs) can decrease the time to speciation and determination of vancomycin resistance but may not lead to improved antibiotic stewardship. METHODS: Over 3 years, the time to administration of institutionally preferred antibiotics (IPT) for patients with E-BSI was evaluated and compared between 3 intervention groups: before (baseline) and after implementation of a rapid diagnostic (BC-GP), and the use of BC-GP with an Infectious Diseases (ID) fellow-driven consultative intervention (BC-GP + ID). RESULTS: A total of 110 patients (63 baseline, 13 BC-GP, 34 BC-GP + ID) with E-BSI were evaluated. Evaluation of Enterococcus faecium BSI showed that the time IPT was significantly reduced with BC-GP + ID by 10.6 h from baseline (P = 0.02) and 5.4 h from BC-GP (P = 0.04). CONCLUSIONS: An ID fellow-driven stewardship intervention was associated with a significant improvement in time to IPT for patients with E. faecium but not E. faecalis BSI.

A Healthcare Improvement Intervention Combining Nucleic Acid Microarray Testing With Direct Physician Response for Management of Staphylococcus aureus Bacteremia.

Background: Nucleic acid microarray (NAM) testing for detection of Staphylococcus aureus bacteremia (SAB) and S. aureus resistance gene determinants can reduce time to targeted antibiotic administration. Evidence-based management of SAB includes bedside infectious diseases (ID) consultation. As a healthcare improvement initiative at our institution, with the goal of improving management and outcomes for subjects with SAB, we implemented NAM with a process for responding to positive NAM results by directly triggered, mandatory ID consultation. Methods: Preintervention, SAB was identified by traditional culture and results passively directed to antibiotic stewardship program (ASP) pharmacists. Postintervention, SAB in adult inpatients was identified by Verigene Gram-Positive Blood Culture test, results paged directly to ID fellow physicians, and consultation initiated immediately. In the new process, ASP assisted with management after the initial consultation. A single-center, retrospective, pre-/postintervention analysis was performed. Results: One hundred six preintervention and 120 postintervention subjects were assessed. Time to ID consultation after notification of a positive blood culture decreased 26.0 hours (95% confidence interval [CI], 45.1 to 7.1 hours, P < .001) postintervention compared with preintervention. Time to initiation of targeted antibiotic decreased by a mean of 21.2 hours (95% CI, 31.4 to 11.0 hours, P < .001) and time to targeted antibiotics for methicillin-sensitive S. aureus decreased by a mean of 40.7 hours (95% CI, 58.0 to 23.5 hours, P < .001). The intervention was associated with lower in-hospital (13.2% to 5.8%, P = .047) and 30-day (17.9% to 8.3%, P = .025) mortality. Conclusions: Compared with an ASP-directed response to traditionally detected SAB, an efficient physician response to NAM was associated with improved care and outcomes for SAB.

Use of a Toxin Neutralization Assay To Characterize the Serologic Response to Adenylate Cyclase Toxin after Infection with Bordetella pertussis.

Adenylate cyclase toxin (ACT) is an essential virulence factor of Bordetella pertussis, and antibodies to ACT protect against B. pertussis infection in mice. The toxin is therefore a strong candidate antigen for addition to future acellular pertussis vaccines. In order to characterize the functionality of the immunologic response to ACT after infection, we developed an assay for testing the ability of serum samples from subjects infected with B. pertussis to neutralize ACT-induced cytotoxicity in J774 macrophage cells. Baboons develop neutralizing anti-ACT antibodies following infection with B. pertussis, and all sera from baboons with positive anti-ACT IgG enzyme-linked immunosorbent assay (ELISA) results neutralized ACT cytotoxicity. The toxin neutralization assay (TNA) was positive in some baboon sera in which ELISA remained negative. Of serum samples obtained from humans diagnosed with pertussis by PCR, anti-ACT IgG ELISA was positive in 72%, and TNA was positive in 83%. All samples positive for anti-ACT IgG ELISA were positive by TNA, and none of the samples from humans without pertussis neutralized toxin activity. These findings indicate that antibodies to ACT generated following infection with B. pertussis consistently neutralize toxin-induced cytotoxicity and that TNA can be used to improve understanding of the immunologic response to ACT after infection or vaccination.

Complete Genome Sequence of Bordetella pertussis Strain VA-190 Isolated from a Vaccinated 10-Year-Old Patient with Whooping Cough.

The number of cases of pertussis has increased in the United States despite vaccination. We present the genome of an isolate of Bordetella pertussis from a vaccinated patient from Virginia. The genome was sequenced by long-read methodology and compared to that of a clinical isolate used for laboratory studies, D420.

Review of the neutrophil response to Bordetella pertussis infection.

The nature and timing of the neutrophil response to infection with Bordetella pertussis is influenced by multiple virulence factors expressed by the bacterium. After inoculation of the host airway, the recruitment of neutrophils signaled by B. pertussis lipooligosaccharide (LOS) is suppressed by pertussis toxin (PTX). Over the next week, the combined activities of PTX, LOS and adenylate cyclase toxin (ACT) result in production of cytokines that generate an IL-17 response, promoting neutrophil recruitment which peaks at 10-14 days after inoculation in mice. Arriving at the site of infection, neutrophils encounter the powerful local inhibitory activity of ACT, in conjunction with filamentous hemagglutinin. With the help of antibodies, neutrophils contribute to clearance of B. pertussis, but only after 28-35 days in a naïve mouse. Studies of the lasting, antigen-specific IL-17 response to infection in mice and baboons has led to progress in vaccine development and understanding of pathogenesis. Questions remain about the mediators that coordinate neutrophil recruitment and the mechanisms by which neutrophils overcome B. pertussis virulence factors.