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The prevalence and effects of inappropriate empirical antibiotic therapy for bloodstream infections are unclear. We aimed to establish the population-level burden, predictors, and mortality risk of in-vitro susceptibility-discordant empirical antibiotic therapy among patients with bloodstream infections. Our retrospective cohort analysis of electronic health record data from 131 hospitals in the USA included patients with suspected—and subsequently confirmed—bloodstream infections who were treated empirically with systemic antibiotics between Jan 1, 2005, and Dec 31, 2014. We included all patients with monomicrobial bacteraemia caused by common bloodstream pathogens who received at least one systemic antibiotic either on the day blood cultures were drawn or the day after, and for whom susceptibility data were available. We calculated the prevalence of discordant empirical antibiotic therapy—which was defined as receiving antibiotics on the day blood culture samples were drawn to which the cultured isolate was not susceptible in vitro—overall and by hospital type by using regression tree analysis. We used generalised estimating equations to identify predictors of receiving discordant empirical antibiotic therapy, and used logistic regression to calculate adjusted odds ratios for the relationship between in-hospital mortality and discordant empirical antibiotic therapy. 21 608 patients with bloodstream infections received empirical antibiotic therapy on the day of first blood culture collection. Of these patients, 4165 (19%) received discordant empirical antibiotic therapy. Discordant empirical antibiotic therapy was independently associated with increased risk of mortality (adjusted odds ratio 1·46 [95% CI, 1·28–1·66]; p<0·0001), a relationship that was unaffected by the presence or absence of resistance or sepsis or septic shock. Infection with antibiotic-resistant species strongly predicted receiving discordant empirical therapy (adjusted odds ratio 9·09 [95% CI 7·68–10·76]; p<0·0001). Most incidences of discordant empirical antibiotic therapy and associated deaths occurred among patients with bloodstream infections caused by Staphylococcus aureus or Enterobacterales. Approximately one in five patients with bloodstream infections in US hospitals received discordant empirical antibiotic therapy, receipt of which was closely associated with infection with antibiotic-resistant pathogens. Receiving discordant empirical antibiotic therapy was associated with increased odds of mortality overall, even in patients without sepsis. Early identification of bloodstream pathogens and resistance will probably improve population-level outcomes. US National Institutes of Health, US Centers for Disease Control and Prevention, and US Agency for Healthcare Research and Quality.

U.S. laws enacted since 1983 have aimed to enhance the development and marketing of new pharmaceutical products. We thoroughly characterized all new molecular entities, therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA) during the period 1980–2022 in the context of these laws and regulations. Throughout the study period, the FDA approved 1355 new pharmaceutical products. The median FDA review time decreased from 26.6 months prior to the Prescription Drug User Fee Act (1992), which authorized the FDA to collect fees from drug companies to 9.9 months after the Food and Drug Administration Safety and Innovation Act (2012), which created new designations that eliminated the requirement for evidence of added therapeutic benefit for FDA expedited drug review. The greatest increase in approvals occurred in antineoplastic and immunomodulating drugs, biologics, and orphan drugs. More than half of new drug approvals benefited from regulatory designations and pathways that did not require addressing unmet medical needs or demonstrating therapeutic benefit over available alternatives. The legislative goal of bringing more drugs to the market faster has been achieved. Further studies are needed to determine the therapeutic value to patients of new drugs approved using expedited approval pathways.

Background Degenerative disc disease (DDD) is a common disorder that can lead to chronic lower back pain (CLBP). The Oswestry Disability Index (ODI) is a well-established instrument for diseases of the lumbar spine and lower back pain (LBP), covering pain intensity and pain-related disability. This study evaluated the content validity of the modified electronic ODI among patients with DDD and CLBP in the United States (US). Method Cognitive interviews were conducted with 12 participants from the US diagnosed with DDD and CLBP using a semi-structured interview guide to assess the comprehension and relevance of the ODI. Concept saturation was achieved by the 12th interview. Results Twelve participants (mean age 40 years old, standard deviation 11 years) including 11 females provided interpretations of the instructions and for each section that were aligned with the intended meanings (11–12/12, ≥ 92%). Sections were relevant to participants’ experience (11–12/12, ≥ 92%), with the sex life section being less relevant (9/12, 75%). Response options were easy to understand. Participants’ interpretations aligned with response options’ intended meanings in 7/10 sections, with less alignment in the lifting, social life, sex life sections due to perceived similarities in ≥ 2 response options. Participants used different recall periods across sections, which was often related to the absence of experiencing the activity at the time of the interview. Most (7/9, 78%) preferred the use of a one-week recall period. Conclusions This study confirms the content validity of the ODI in patients with DDD. The ODI with a seven-day recall period would be more appropriate for use in this population to evaluate patient outcomes in a clinical trial.

Abstract Background Resistance to all first-line antibiotics necessitates the use of less effective or more toxic \"reserve\" agents. Gram-negative bloodstream infections (GNBSIs) harboring such difficult-to-treat resistance (DTR) may have higher mortality than phenotypes that allow for ≥1 active first-line antibiotic. Methods The Premier Database was analyzed for inpatients with select GNBSIs. DTR was defined as intermediate/resistant in vitro to all ß-lactam categories, including carbapenems and fluoroquinolones. Prevalence and aminoglycoside resistance of DTR episodes were compared with carbapenem-resistant, extended-spectrum cephalosporin-resistant, and fluoroquinolone-resistant episodes using CDC definitions. Predictors of DTR were identified. The adjusted relative risk (aRR) of mortality was examined for DTR, CDC-defined phenotypes susceptible to ≥1 first-line agent, and graded loss of active categories. Results Between 2009-2013, 471 (1%) of 45011 GNBSI episodes at 92 (53.2%) of 173 hospitals exhibited DTR, ranging from 0.04% for Escherichia coli to 18.4% for Acinetobacter baumannii. Among patients with DTR, 79% received parenteral aminoglycosides, tigecycline, or colistin/polymyxin-B; resistance to all aminoglycosides occurred in 33%. Predictors of DTR included urban healthcare and higher baseline illness. Crude mortality for GNBSIs with DTR was 43%; aRR was higher for DTR than for carbapenem-resistant (1.2; 95% confidence interval, 1.0-1.4; P = .02), extended-spectrum cephalosporin-resistant (1.2; 1.1-1.4; P = .001), or fluoroquinolone-resistant (1.2; 1.0-1.4; P = .008) infections. The mortality aRR increased 20% per graded loss of active first-line categories, from 3-5 to 1-2 to 0. Conclusion Nonsusceptibility to first-line antibiotics is associated with decreased survival in GNBSIs. DTR is a simple bedside prognostic measure of treatment-limiting coresistance. Resistance to all first-line agents or difficult-to-treat resistance (DTR) was observed in 1% of gram-negative bacteremias. DTR was identified at half the hospitals; nearly 80% of patients with DTR received \"reserve\" agents. Mortality risk increased with decreasing active first-line categories.

Evidence-based needs assessments for novel antibiotics against highly-resistant Gram-negative infections (GNIs) are scarce. We aimed to use real-world data from an electronic health record repository to identify treatment opportunities in US hospitals for GNIs resistant to all first-line drugs. For this retrospective cohort study, population estimates with an unmet need for novel Gram-negative antibiotics were quantified using the Cerner Health Facts database (2009–15), aggregating episodes of infection in US hospitals with pathogens displaying difficult-to-treat resistance (DTR; resistance to carbapenems, other β-lactams, and fluoroquinolones) and episodes involving empirical coverage with reserve drugs (colistin or polymyxin B and aminoglycosides). Episodes displaying extended-spectrum cephalosporin resistance (ECR) were also estimated. Episodes were multiplied by site-specific and fixed 14-day treatment durations for conservative and liberal days-of-therapy (DOT) estimates and stratified by site and taxon. Hospital type-specific DOT rates were reliability adjusted to account for random variation; cluster analyses quantified contribution from outbreaks. Across 2 996 271 inpatient encounters and 134 hospitals, there were 1352 DTR-GNI episodes, 1765 episodes involving empirical therapy with colistin or polymyxin B, and 16 632 episodes involving aminoglycosides. Collectively, these yielded 39·0 (conservative estimate) to 138·2 (liberal estimate) DOT per 10 000 encounters for a novel DTR-GNI-targeted drug, whereas greater treatment opportunities were identified for ECR (six times greater) and β-lactam susceptible GNIs (70 times greater). The most common DTR-GNI site and pathogen was lower respiratory (14·3 [43·3%] of 33 DOT per 10 000 encounters) and Pseudomonas aeruginosa (522 [38·1%] of 1371 episodes), whereas Enterobacteriaceae urinary-tract infections dominated the ECR or carbapenem-sparing niche (59·0% [5589 of 9535 episodes]) equating to 210·7 DOT per 10 000 encounters. DTR Stenotrophomonas maltophilia, Burkholderia spp, and Achromobacter spp represented less than 1 DOT per 10 000 encounters each. The estimated need for DTR-GNI-targeted antibiotics saw minor contributions by outbreaks and varied from 0·5 to 73·1 DOT per 10 000 encounters by hospital type. Suspected or documented GNIs with no or suboptimal treatment options are relatively infrequent. Non-revenue-based strategies and innovative trial designs are probably essential to the development of antibiotics with improved effectiveness for these GNIs. Center for Drug Evaluation and Research, US Food and Drug Administration; Intramural Research Program, National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.

Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use.

Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of ≥1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of ≥1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms. IMPORTANCE This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza. This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza.

ObjectiveTo describe demographics, causative pathogens, hospitalisation, mortality and antimicrobial resistance (AMR) of bacterial bloodstream infections (BSIs) among beneficiaries in the global US Military Health System (MHS), a single-provider healthcare system with 10-year longitudinal follow-up.DesignRetrospective cohort study.SettingClinical and demographic data collected from the MHS Data Repository and collated with microbiological data obtained from the Defense Centers for Public Health-Portsmouth. Participants: 12 748 MHS beneficiaries diagnosed with 15 357 bacterial BSIs (2010–2019).Main outcome(s) and measure(s)Demographic data and diagnosis codes preceding BSI episodes and during hospitalisations were collected. Inpatient admission data identified acute clinical diagnoses, intensive care unit (ICU) admission and mortality. BSI pathogens were evaluated for AMR, including difficult-to-treat resistance (DTR). Crude mortality trends were assessed.ResultsThe decade analysed included 15 357 BSI episodes in 12 748 patients; 6216 patients (48.8%) were≥65 years and 83.7% of episodes had≥1 comorbidity (12 856 of 15 357). Approximately 29% of episodes with hospitalisation required ICU admission and∼34% had concurrent urinary tract infections. Pathogen distribution was 53% and 47% for Gram-positive bacteria and Gram-negative bacilli (GNB), respectively. Inpatient mortality was 4.4%, and at 1 year was 23.4%; 0.5% (16 of 2977) of deaths were associated with DTR GNB. Among an average 8 145 778 individuals receiving care annually in the MHS, annual rates of overall BSI, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp and DTR GNB BSI were 18.9, 1.30, 0.25 and 0.05 per 100 000 beneficiaries, respectively. Over the decade, annual mortality did not significantly increase for any pathogen and decreased by∼2% for overall BSI (p=0.024) and∼3% for lactose-fermenting GNB BSI (p=0.048).ConclusionsIn the global US MHS, the mortality burden associated with BSI was substantial (approximately one in four dying at 1 year), relatively unchanged over a decade, and associated with older age and comorbidities. First-line treatment options remained available for 99.7% of BSIs. Population-level improvements in BSI survival might be maximally influenced by focusing on prevention, early detection, prompt antibiotics and other novel therapies not contingent on in vitro activity.

Background Information about the impact of respiratory syncytial virus (RSV) on quality of life in older adults is limited. This study characterized the patient experience of RSV illness in USA older adults and assessed the content validity of the InFLUenza Patient Reported Outcome (FLU‐PRO) in this population. Methods This qualitative, non‐interventional, cross‐sectional study included hybrid concept elicitation and cognitive debriefing interviews with 30 individuals (age ≥50 years) with polymerase chain reaction‐confirmed RSV diagnosed within 6 months of screening. Targeted literature review was first conducted to inform the development of interview materials. Webcam or telephone interviews were conducted by qualitative researchers using a semistructured interview guide. Interview transcripts were coded and analyzed using Excel and NVivo software. Results All participants reported impacts on daily activities, social activities, and relationships during RSV disease. Physical functioning was impaired in 25 (83%) participants, and 18 (60%) reported not engaging in leisure activities/hobbies. All nine participants who were working reported major impacts on work. Most (n = 28; 93%) described emotional impacts. A majority (n = 19; 63%) reported symptoms lasting beyond the acute disease stage from a week to >1 month. Symptom concepts reported generally matched FLU‐PRO items and domains. Cognitive debriefing indicated that FLU‐PRO was easy to understand and captured participants' experiences of RSV illness. Conclusions This study indicates that RSV disease in adults aged ≥50 years in the USA has substantial impacts on daily life and that the concepts included in FLU‐PRO are appropriate and fit for purpose as a measure of RSV symptoms in this population.

The use of antimicrobials in food animals creates an important source of antimicrobial-resistant bacteria that can spread to humans through the food supply. Improved management of the use of antimicrobials in food animals, particularly reducing the usage of those that are “critically important” for human medicine, is an important step toward preserving the benefits of antimicrobials for people. The World Health Organization has developed and applied criteria to rank antimicrobials according to their relative importance in human medicine. Clinicians, regulatory agencies, policy makers, and other stakeholders can use this ranking when developing risk management strategies for the use of antimicrobials in food production animals. The ranking allows stakeholders to focus risk management efforts on drugs used in food animals that are the most important to human medicine and, thus, need to be addressed most urgently, such as fluoroquinolones, macrolides, and third- and fourth-generation cephalosporins.