Citations

Abstract In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0.

Abstract Background Community-acquired pneumonia (CAP) in children is usually treated with 10 days of antibiotics. Shorter antibiotic courses may be beneficial if proven effective, with potentially fewer antibiotic adverse effects and decreased antibiotic exposure. Methods This randomized, double-blind, placebo-controlled superiority trial (NCT02891915) compared a strategy of short vs standard course ß-lactam therapy for outpatient CAP in children ages 6–71 months. Children demonstrating clinical improvement by day 3–5 of initial therapy were considered for enrollment. Enrolled children were randomized 1:1 to receive either 5 additional days of the originally prescribed antibiotic (standard) or matching placebo (short). The Desirability of Outcome Ranking (DOOR; PMID: 26113652) was the primary outcome, and was defined by classifying the global experience of children into an ordinal clinical response (OCR) that combined the response to CAP treatment and antibiotic adverse effects 11–15 days after the start of therapy. For those subjects with equivalent OCR, documented days of antibiotic administration was used to further rank the desirability of the outcome with the a priori assumption that shorter antibiotic exposure was more desirable. The OCR was a secondary outcome. The intention to treat population was used to estimate the probability of a more desirable outcome for the strategy of short vs. standard course therapy for both outcomes. Results 385 children were enrolled; 380 had complete data for analysis. Baseline characteristics were similar between the two strategies. In both strategies, > 90% of children had an adequate response to CAP treatment and most antibiotic adverse effects were minor (Table). In the OCR analysis, short course therapy had a 48% probability (95% CI: 42%-53%) of a more desirable outcome. In the DOOR analysis, short course therapy was superior to standard therapy with a 69% probability (95% CI: 63%-72%; p< 0.001) of a more desirable outcome. Conclusion Among children with CAP demonstrating initial clinical improvement with outpatient therapy, both strategies had a similar response to CAP treatment and antibiotic adverse effects, but short course therapy was superior in our a priori defined outcome that incorporated decreased antibiotic exposure. Disclosures Emmanuel B. Walter, MD, MPH, Moderna (Grant/Research Support)Pfizer (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) W. Charles Huskins, MD, MSc, ADMA Biologics (Consultant)Pfizer, Inc (Consultant)

AbstractClinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Abstract Background Pharyngeal and rectal Neisseria gonorrhoeae and Chlamydia trachomatis play important roles in infection and antibacterial resistance transmission, but no US Food and Drug Administration (FDA)–cleared assays for detection at these sites existed prior to this study. The objective was to estimate performance of assays to detect those infections in pharyngeal and rectal specimens to support regulatory submission. Methods We performed a cross-sectional, single-visit study of adults seeking sexually transmitted infection testing at 9 clinics in 7 states. We collected pharyngeal and rectal swabs from participants. The primary outcome was positive and negative percent agreement for detection of N. gonorrhoeae and C. trachomatis for 3 investigational assays compared to a composite reference. Secondary outcomes included positivity as well as positive and negative predictive values and likelihood ratios. Subgroup analyses included outcomes by symptom status and sex. Results A total of 2598 participants (79% male) underwent testing. We observed N. gonorrhoeae positivity of 8.1% in the pharynx and 7.9% in the rectum and C. trachomatis positivity of 2.0% in the pharynx and 8.7% in the rectum. Positive percent agreement ranged from 84.8% to 96.5% for different anatomic site infection combinations, whereas negative percent agreement was 98.8% to 99.6%. Conclusions This study utilized a Master Protocol to generate diagnostic performance data for multiple assays from different manufacturers in a single study population, which ultimately supported first-in-class FDA clearance for extragenital assays. We observed very good positive percent agreement when compared to a composite reference method for the detection of both pharyngeal and rectal N. gonorrhoeae and C. trachomatis. Clinical Trials Registration NCT02870101.

Abstract Rationale Prompt diagnosis of invasive fungal infections is important because of the associated morbidity and mortality; however, diagnosis is challenging because of the nonspecific symptoms and radiographic findings. Objectives To conduct a systematic review and meta-analysis of studies that evaluated the diagnostic accuracy of serum and bronchoalveolar lavage (BAL) galactomannan (GM) and serum or BAL polymerase chain reaction (PCR) in patients with suspected invasive aspergillosis (IA), β-d-glucan in critically ill patients at risk for candidiasis or candidemia, and serology testing and antigen detection in patients with endemic mycoses (histoplasmosis, blastomycosis, and coccidioidomycosis). Methods Studies were selected and appraised by pairs of reviewers. Bivariate random effects meta-analysis was used to generate pooled sensitivity, specificity, and diagnostic likelihood ratios. Results Serum GM in patients with impaired immunity suspected of having IA had sensitivity of 0.71 (95% confidence interval [CI], 0.64–0.78) and specificity of 0.89 (95% CI, 0.84–0.92). A cutoff of 1 optical density index yielded optimal sensitivity and specificity. BAL GM in patients with impaired immunity suspected of having IA had sensitivity of 0.84 (95% CI, 0.73–0.91) and specificity of 0.88 (95% CI, 0.81–0.91). Serum or whole-blood PCR in immunocompromised patients with suspected IA had sensitivity of 0.81 (95% CI, 0.73–0.86) and specificity of 0.79 (95% CI, 0.68–0.86). BAL PCR in patients at high risk for IA had high sensitivity of 0.90 (95% CI, 0.77–0.96) and specificity of 0.96 (95% CI, 0.93–0.98) for diagnosing IA. β-d-glucan assay in patients in the intensive care unit at risk for invasive candidiasis or candidemia had sensitivity of 0.81 (95% CI, 0.74–0.86) and specificity of 0.60 (95% CI, 0.49–0.71). Data on diagnostic accuracy of antigen detection and serology testing for endemic mycoses were limited and heterogeneous (varied according to test, patient immunity, and suspected endemic disease). Conclusions The diagnosis of invasive fungal infections remains a challenge. Various serum and BAL markers can aid in diagnosis. This evidence supports the development of clinical practice recommendations by the American Thoracic Society.

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1 –/+ mice inhibited d-flow–induced atherogenesis. In sum, EC activation and ER stress–mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Abstract Background Achieving appropriate therapy for BSI caused by Gram-negative rods (GNR) is challenging. The availability of AST results allows de-escalation from broad- to narrow-spectrum agents. De-escalation is a goal of antimicrobial stewardship (AS). Through the analysis of inpatient BL antibiotic regimens in a nationwide cohort of patients with Escherichia coli and Klebsiella pneumoniae BSI, we compared the relative spectrum of empiric and definitive treatments to AST results and identified opportunities for de-escalation. Methods Using a cohort of patients hospitalized within VHA, we identified patients with a blood culture positive for E. coli or K. pneumoniae between 2006 and 2015. We analyzed the subset of patients receiving inpatient BLs before and after Gram stain (GS) and AST results. BLs were grouped into five tiers of increasing spectrum, both with and without a requirement for anaerobic activity (Figure 1). Tiers of BLs across the treatment periods were summarized and compared with the lowest-spectrum tier with an active agent. Rates of inactive, optimal, and overly broad BL therapy were summarized by organism and treatment period. Results Of 36,531 BSI identified, we analyzed a subset of 10,825 (7,100 E. coli, 3,725 K. pneumoniae) that met our inclusion criteria (Figure 2). The use of inactive BL agents decreased across time, falling from 11% in early empiric to 4.5% in definitive treatments. The proportion of patients receiving the narrowest available effective BL therapy (“optimal” therapy) increased from 5% to 8% after GS results and to 14% after AST results (Figure 3). De-escalation to optimal therapy after AST results was observed in only 7% of opportunities. If anaerobic activity was required, a smaller proportion of cases would be considered overtreated in the empiric periods (45–46%), but de-escalation after AST results was observed in only 10% of these cases. Conclusion Changes in BL agents across treatment periods reflect an escalation to active treatment, but the absence of de-escalation after AST results was available. This was true both with and without considering a need for anaerobic activity. Expansion of this analysis to include additional classes such as fluoroquinolones may reveal opportunities for AS and de-escalation to optimal therapy in the treatment of E. coli and K. pneumoniae BSI. Disclosures R. Patel, CD Diagnostics, BioFire, Curetis, Merck, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, Allergan, and The Medicines Company: Grant Investigator, Research grant – monies paid to Mayo Clinic. Curetis, Specific Technologies, Selux Dx, GenMark Diagnostics, PathoQuest and Genentech: Consultant and Scientific Advisor, Consulting fee – monies paid to Mayo Clinic. ASM and IDSA: Travel reimbursement and editor’s stipends, Travel reimbursement and editor’s stipends. NBME, Up-to-Date and the Infectious Diseases Board Review Course: Varies, Honoraria. Mayo Clinic: Employee, Salary. R. Banerjee, Accelerate Diagnostics, Biomerieux, BioFire: Grant Investigator, Research grant and Research support.

AbstractBackgroundOvercoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa.MethodsIn this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer β-lactam/β-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO).ResultsWe found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA).ConclusionsThe diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.