Trajectories of Sacubitril/Valsartan Adherence Among Medicare Beneficiaries With Heart Failure.

Background: Sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNi), improves heart failure (HF) outcomes, yet real-world adherence patterns are not well understood. Objectives: The purpose of this study was to analyze longitudinal patterns of adherence to ARNis in patients with HF and to identify factors associated with adherence patterns. Methods: Using Medicare beneficiaries from 2015 to 2018, we included patients diagnosed with HF who initiated an ARNi. A group-based trajectory model was constructed to identify adherence patterns during follow-up. We used multivariable logistic regression to investigate factors associated with membership in each adherence trajectory group. Results: Among 9,475 eligible beneficiaries (age 77 ± 7 years, 34% female), we identified 5 distinct ARNi adherence trajectories, characterized as: immediate discontinuers, who discontinued treatment within the first 3 months (12%); early discontinuers, who discontinued treatment in months 4 to 7 (10%); late discontinuers, who discontinued treatment in months 7 to 10 (12%); intermittently adherent patients (12%); and consistently adherent patients (54%). The first 4 groups were collectively categorized as nonconsistent adherents. Living in a socioeconomically disadvantaged area, ie, a county with the top 20% of Area Deprivation Index (adjusted OR [aOR]: 1.12 [95% CI: 1.00-1.24]) and Black race (aOR: 1.36, [95% CI: 1.18-1.56]) were associated with a higher likelihood of being nonconsistently adherent. Receiving prescriptions from a cardiologist (aOR: 0.64 [95% CI: 0.57-0.73]) was associated with a lower likelihood of suboptimal ARNi adherence. Conclusions: Half of ARNi users were not consistently adherent to the drug in the first year after treatment initiation. There exist significant racial and socioeconomic inequities in longitudinal adherence to ARNi.

Clinical characteristics, predisposing factors and outcomes for Enterococcus faecalis versus Enterococcus faecium bloodstream infections: a prospective multicentre cohort study.

PURPOSES: Enterococcal BSI is associated with significant morbidity and mortality, with fatality rates of approximately 20-30%. There are microbiological and clinical differences between E. faecalis and E. faecium infections. The aim of this study was to investigate differences in predisposing factors for E. faecalis and E. faecium BSI and to explore prognostic factors. METHODS: This study was a post-hoc analysis of PROBAC, a Spanish prospective, multicenter, cohort in 2016-2017. Patients with E. faecalis or E. faecium BSI were eligible. Independent predictors for BSI development in polymicrobial and monomicrobial BSI and in-hospital mortality in the monomicrobial group were identified by logistic regression. RESULTS: A total of 431 patients were included. Independent factors associated with E. faecium BSI were previous use of penicillins (aOR 1.99 (95% CI 1.20-3.32)) or carbapenems (2.35 (1.12-4.93)), hospital-acquired BSI (2.58 (1.61-4.12)), and biliary tract source (3.36 (1.84-6.13)), while congestive heart failure (0.51 (0.27-0.97)), cerebrovascular disease (0.45 (0.21-0.98)), and urinary tract source (0.49 (0.26-0.92)) were associated with E. faecalis BSI. Independent prognostic factors for in-hospital mortality in E. faecalis BSI were Charlson Comorbidity Index (1.27 (1.08-1.51)), SOFA score (1.47 (1.24-1.73)), age (1.06 (1.02-1.10)), and urinary/biliary source (0.29 (0.09-0.90)). For E. faecium BSI, only SOFA score (1.34 (1.14-1.58) was associated with in-hospital mortality. CONCLUSIONS: The factors associated with E. faecium and E. faecalis BSI are different. These variables may be helpful in the suspicion of one or other species for empiric therapeutic decisions and provide valuable information on prognosis.

COVID-19 Diagnosis, Oral Anticoagulation, and Stroke Risk in Patients with Atrial Fibrillation.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been associated with an increased risk of stroke. It remains unclear whether the risk of stroke associated with a diagnosis of COVID-19 differed with oral anticoagulation (OAC) use. The aim of this study was to evaluate the association between COVID-19 infection, OAC use, and stroke in patients with atrial fibrillation (AF). METHODS: A retrospective cohort study was conducted in individuals with established AF using data from Optum's deidentified Clinformatics® Data Mart Database. Cox proportional hazard models with time-dependent variables were employed to assess the association between possession of OAC, COVID-19 diagnosis in both inpatient and outpatient setting, and time to ischemic stroke. RESULTS: A total of 561,758 individuals aged 77 ± 10 were included in the study, with a mean follow up time of 1.3 years. OAC use was associated with a reduced stroke risk [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.82-0.88]. COVID-19 infection was associated with an increased risk of stroke (HR 2.11, 95% CI 1.87-2.38); this increased risk was particularly pronounced for patients diagnosed with an inpatient diagnosis of COVID-19 (HR 3.95, 95% CI 3.33-4.68). There was no significant interaction between OAC use and COVID-19 diagnosis (p value = 0.96). As a result, the relative increase in stroke risk associated with COVID-19 did not differ between patients on OAC (HR 2.12; 95% CI 1.71-2.62) and those not on OAC (HR 2.11; 95% CI 1.83-2.43). CONCLUSION: In a nationwide sample of patients with established AF, we found the relative increase in stroke risk associated with COVID-19 was independent of OAC use.

Cheaper is not always better: Drug shortages in the United States and a value-based solution to alleviate them.

Drug shortages threaten patients' access to medications and are associated with adverse health outcomes and increased costs. Drug shortages disproportionately occur among generic drugs of limited profitability, most notably drugs administered by injection. In this perspective, we discuss how reimbursement and purchasing practices that were meant to create an efficient marketplace for generics have generated strong price pressure that threatens profitability in certain markets. We further explain how, faced with limited profitability, manufacturers lack incentives to invest in resilient supply chains, and in some cases, engage in cost-containment strategies or decide to exit the market, ultimately contributing to shortages. We propose the development and implementation of value-based reimbursement to provide needed incentives for drug purchasers and manufacturers to establish a more reliable supply chain as part of the policy solution to reduce the number and extent of drug shortages. This reimbursement model would necessitate the development of a rating system that measures supply chain resilience and maturity for each generic product. This rating would then be applied as a value-based modifier to reimbursement rates for generic products. The proposed model would result in higher reimbursement rates for generic products from more dependable supply chains, generating incentives for manufacturers to invest in supply chain resiliency. We propose the application of this reimbursement system originally in Medicare given Congressional interest on reforming Medicare payment to prevent drug shortages.

Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease.

INTRODUCTION: Bumetanide, a loop diuretic, was identified as a candidate drug for repurposing for Alzheimer's disease (AD) based on its effects on transcriptomic apolipoprotein E signatures. Cross-sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, temporality between bumetanide exposure and AD development has not been established. METHODS: We evaluated Medicare claims data using Cox proportional hazards regression to evaluate the association between time-dependent use of bumetanide and time to first AD diagnosis while controlling for patient characteristics. Multiple sensitivity analyses were conducted to test the robustness of the findings. RESULTS: We sampled 833,561 Medicare beneficiaries, 60.8% female, with mean (standard deviation) age of 70.4 (12). Bumetanide use was not significantly associated with AD risk (hazard ratio 1.05; 95% confidence interval, 0.99-1.10). DISCUSSION: Using a nationwide dataset and a retrospective cohort study design, we were not able to identify a time-dependent effect of bumetanide lowering AD risk. HIGHLIGHTS: Bumetanide was identified as a candidate for repurposing for Alzheimer's disease (AD). We evaluated the association between bumetanide use and risk of AD. We used Medicare data and accounted for duration of bumetanide use. Bumetanide use was not significantly associated with risk of AD.

Price benchmarks of drugs selected for Medicare price negotiation and their therapeutic alternatives.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) are currently negotiating prices with pharmaceutical manufacturers for the first 10 Part D drugs selected for Medicare drug price negotiation. Non-publicly available data, including the net prices of selected drugs and their therapeutic alternatives, will play a central role in the determination of the maximum fair prices (MFPs). OBJECTIVE: To estimate price benchmarks involved in the derivation of the starting point of the CMS initial price offer for the 10 drugs selected for Medicare price negotiation. METHODS: For the 10 drugs selected for negotiation, we reported (1) the list price, (2) the net price after manufacturer discounts, (3) the maximum negotiated price based on the minimum statutory discount, and (4) the ceiling of the MFP, estimated as the lowest of the latter 2. We also estimated net prices for therapeutic alternatives to the selected drugs. Net prices were estimated using peer-reviewed methodology that isolates commercial discounts negotiated between payers and manufacturers from mandatory discounts under government programs. All price benchmarks were estimated at the product level, for 30-day equivalent dosing, using 2021 data. RESULTS: 6 products (apixaban, rivaroxaban, empagliflozin, sacubitril/valsartan, etanercept, and insulin aspart) had therapeutic alternatives with lower net prices, which will be integrated with clinical benefit data in the derivation of initial price offers. The other 4 products (ustekinumab, ibrutinib, sitagliptin, and dapagliflozin) had therapeutic alternatives with higher net prices than the drugs selected for negotiation. For ibrutinib and ustekinumab, prices based on the minimum discounts were considerably lower than the estimated net prices and will likely set the starting point of the initial price offer. For dapagliflozin and sitagliptin, the starting point of the initial price offer will likely resemble their existing net prices. CONCLUSIONS: Our analyses identify different negotiation scenarios for the first 10 drugs selected for Medicare price negotiation, based on key elements involved in the derivation of the initial price offer. Our analyses can help improve transparency in the negotiation process, because the CMS is not required to reveal the information used in the derivation of price offers.

A comprehensive, predictive mortality score for patients with bloodstream infections (PROBAC): a prospective, multicentre cohort study.

OBJECTIVES: Bloodstream infections (BSI) are an important cause of mortality, although they show heterogeneity depending on patients and aetiological factors. Comprehensive and specific mortality scores for BSI are scarce. The objective of this study was to develop a mortality predictive score in BSI based on a multicentre prospective cohort. METHODS: A prospective cohort including consecutive adults with bacteraemia recruited between October 2016 and March 2017 in 26 Spanish hospitals was randomly divided into a derivation cohort (DC) and a validation cohort (VC). The outcome was all-cause 30-day mortality. Predictors were assessed the day of blood culture growth. A logistic regression model and score were developed in the DC for mortality predictors; the model was applied to the VC. RESULTS: Overall, 4102 patients formed the DC and 2009 the VC. Mortality was 11.8% in the DC and 12.34% in the CV; the patients and aetiological features were similar for both cohorts. The mortality predictors selected in the final multivariate model in the DC were age, cancer, liver cirrhosis, fatal McCabe underlying condition, polymicrobial bacteraemia, high-risk aetiologies, high-risk source of infection, recent use of broad-spectrum antibiotics, stupor or coma, mean blood pressure <70 mmHg and PaO2/FiO2 ≤ 300 or equivalent. Mortality in the DC was <2% for ≤2 points, 6%-14% for 3-7 points, 26%-45% for 8-12 points and ≥60% for ≥13 points. The predictive score had areas under the receiving operating curves of 0.81 (95% CI 0.79-0.83) in the DC and 0.80 (0.78-0.83) in the VC. CONCLUSIONS: A 30 day mortality predictive score in BSI with good discrimination ability was developed and internally validated.

Differences in clinical outcomes of bloodstream infections caused by Klebsiella aerogenes, Klebsiella pneumoniae and Enterobacter cloacae: a multicentre cohort study.

BACKGROUND: Klebsiella aerogenes has been reclassified from Enterobacter to Klebsiella genus due to its phenotypic and genotypic similarities with Klebsiella pneumoniae. It is unclear if clinical outcomes are also more similar. This study aims to assess clinical outcomes of bloodstreams infections (BSI) caused by K. aerogenes, K. pneumoniae and Enterobacter cloacae, through secondary data analysis, nested in PRO-BAC cohort study. METHODS: Hospitalized patients between October 2016 and March 2017 with monomicrobial BSI due to K. aerogenes, K. pneumoniae or E. cloacae were included. Primary outcome was a composite clinical outcome including all-cause mortality or recurrence until 30 days follow-up. Secondary outcomes were fever ≥ 72 h, persistent bacteraemia, and secondary device infection. Multilevel mixed-effect Poisson regression was used to estimate the association between microorganisms and outcome. RESULTS: Overall, 29 K. aerogenes, 77 E. cloacae and 337 K. pneumoniae BSI episodes were included. Mortality or recurrence was less frequent in K. aerogenes (6.9%) than in E. cloacae (20.8%) or K. pneumoniae (19.0%), but statistical difference was not observed (rate ratio (RR) 0.35, 95% CI 0.08 to 1.55; RR 0.42, 95% CI 0.10 to 1.71, respectively). Fever ≥ 72 h and device infection were more common in K. aerogenes group. In the multivariate analysis, adjusted for confounders (age, sex, BSI source, hospital ward, Charlson score and active antibiotic therapy), the estimates and direction of effect were similar to crude results. CONCLUSIONS: Results suggest that BSI caused by K. aerogenes may have a better prognosis than E. cloacae or K. pneumoniae BSI.

Mortality impact of further delays in active targeted antibiotic therapy in bacteraemic patients that did not receive initial active empiric treatment: Results from the prospective, multicentre cohort PROBAC.

OBJECTIVES: The early initiation of the empirical antibiotic treatment and its impact on mortality in patients with bacteraemia has been extensively studied. However, information on the impact of precocity of the targeted antibiotic treatment is scarce. We aimed to study the impact of further delay in active antibiotic therapy on 30-day mortality among patients with bloodstream infection who had not received appropriate empirical therapy. DESIGN: We worked with PROBAC cohort (prospective and compound by patients from 26 different Spanish hospitals). We selected a total of 1703 patients, who survived to day 2 without having received any active antibiotic therapy against the causative pathogen. RESULTS: The 30-day mortality was 14% (238 patients). The adjusted odds of mortality increased for every day of delay, from 1.53 (95% confidence interval (CI) 1.13-2.08) for day 3 or after to 11.38 (95% CI 7.95-16.38) for day 6 or after. CONCLUSION: We concluded that among patients who had not received active treatment within the first 2 days of blood culture collection, additional delays in active targeted therapy were associated with increased mortality. These results emphasize the importance of active interventions in the management of patients with bloodstream infections.

Advancing Access to Cell and Gene Therapies in Medicaid.

This Viewpoint presents the components of the payment model and the implementation challenges among the Center for Medicare and Medicaid Innovation, state Medicaid agencies, patients, and manufacturers.

COVID-19 pandemic and trends in clinical outcomes and medication use for patients with established atrial fibrillation: A nationwide analysis of claims data.

Study objective: The COVID-19 pandemic disrupted multiple aspects of the health care system, including the diagnosis and control of chronic conditions. This study aimed to quantify pandemic-related changes in the rates of clinical events among patients with atrial fibrillation (AF). Design/setting/participants: In this retrospective cohort study, we identified individuals with established AF at any time before 2019 using de-identified Optum's Clinformatics® Data Mart, and followed them from 3/18/2019 to death, or disenrollment, or the end of the study (09/30/2021). Main outcome: Rates of clinical event, including all-cause hospitalization, ischemic stroke, and bleeding. We constructed interrupted time series to test changes in outcomes after the onset of the COVID-19 pandemic (3/11/2020, date of pandemic declaration). We then identified the first month after the start of the pandemic in which outcomes returned to pre-pandemic levels. Results: A total of 561,758 patients, with a mean age of 77 ± 9.9 years, were included in the study. The monthly incidence rate of all-cause hospitalization decreased from 2.8 % in the period immediately before the pandemic declaration to 1.7 % in the period immediately after, with p-value for level change<0.001. The rate of new ischemic stroke diagnoses decreased from 0.28 % in the period immediately before pandemic declaration to 0.20 % in the period immediately after, and the rate of major bleeding diagnoses from 0.81 % to 0.59 %, both p-values for level change<0.01. The incidence rate of ischemic stroke and bleeding events returned to pre-pandemic levels in October and November 2020, respectively. Conclusions: The COVID-19 pandemic was associated with a decrease in health care visits for ischemic stroke and bleeding in a nationwide cohort of patients with established AF.

Racial and Ethnic Inequities in Spatial Access to Pharmacies: A Geographic Information System Analysis.

BACKGROUND: Pharmacy accessibility is crucial for equity in healthcare access because community pharmacists may reach individuals who do not have access to other healthcare providers. OBJECTIVE: To determine whether spatial access to pharmacies differs among racial/ethnic groups across the rural-urban continuum. METHODS: We obtained a 30% random sample of the Research Triangle Institute (RTI) synthetic population, sampled at the census block level. For each individual, we defined optimal pharmacy access as having a driving distance ≤2 miles to the closest pharmacy in urban counties, ≤5 miles in suburban counties, and ≤10 miles in rural counties. We used a logistic regression model to measure the association between race/ethnicity and pharmacy access, while controlling for racial/ethnic composition of the census tract, Area Deprivation Index, income, age, gender, and US region. The model included an interaction between race/ethnicity and urbanicity to evaluate whether racial/ethnic inequities differed across the rural-urban continuum. RESULTS: The sample included 90,749,446 individuals of whom 80.6% had optimal pharmacy access. Racial/ethnic inequities in pharmacy access differed across the rural-urban continuum (p-value for interaction= <0.0001). In rural areas, Black (OR 0.87; 95%CI 0.86-0.87), Hispanic (OR 0.80; 95%CI 0.79-0.80), and Indigenous (OR 0.47; 95%CI 0.47-0.48) individuals had lower odds of optimal pharmacy access, compared to White individuals. Hispanic (OR 0.96; 95%CI 0.96-0.97) and Indigenous individuals (OR 0.75; 95%CI 0.75-0.76) had lower odds of optimal pharmacy access compared to White individuals in suburban areas. In Western states, Asian had lower odds of optimal pharmacy access in suburban (OR 0.88; 95%CI 0.86-0.90) and rural areas (OR 0.91; 95%CI 0.87-0.95) compared to White Individuals. CONCLUSIONS: Racial/ethnic inequities in spatial access to community pharmacies vary between urban and rural communities. Underrepresented racial/ethnic groups have significantly lower pharmacy access in rural and some suburban areas, but not in urban areas.

Association of microbiological factors with mortality in Escherichia coli bacteraemia presenting with sepsis/septic shock: a prospective cohort study.

OBJECTIVES: This study aimed to determine the association of Escherichia coli microbiological factors with 30-day mortality in patients with bloodstream infection (BSI) presenting with a dysregulated response to infection (i.e. sepsis or septic shock). METHODS: Whole-genome sequencing was performed on 224 E coli isolates of patients with sepsis/septic shock, from 22 Spanish hospitals. Phylogroup, sequence type, virulence, antibiotic resistance, and pathogenicity islands were assessed. A multivariable model for 30-day mortality including clinical and epidemiological variables was built, to which microbiological variables were hierarchically added. The predictive capacity of the models was estimated by the area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals (CI). RESULTS: Mortality at day 30 was 31% (69 patients). The clinical model for mortality included (adjusted OR; 95% CI) age (1.04; 1.02-1.07), Charlson index ≥3 (1.78; 0.95-3.32), urinary BSI source (0.30; 0.16-0.57), and active empirical treatment (0.36; 0.11-1.14) with an AUROC of 0.73 (95% CI, 0.67-0.80). Addition of microbiological factors selected clone ST95 (3.64; 0.94-14.04), eilA gene (2.62; 1.14-6.02), and astA gene (2.39; 0.87-6.59) as associated with mortality, with an AUROC of 0.76 (0.69-0.82). DISCUSSION: Despite having a modest overall contribution, some microbiological factors were associated with increased odds of death and deserve to be studied as potential therapeutic or preventive targets.

Drug Shortages Prior to and During the COVID-19 Pandemic.

Importance: Drug shortages are a chronic and worsening issue that compromises patient safety. Despite the destabilizing impact of the COVID-19 pandemic on pharmaceutical production, it remains unclear whether issues affecting the drug supply chain were more likely to result in meaningful shortages during the pandemic. Objective: To estimate the proportion of supply chain issue reports associated with drug shortages overall and with the COVID-19 pandemic. Design, Setting, and Participants: This longitudinal cross-sectional study used data from the IQVIA Multinational Integrated Data Analysis database, comprising more than 85% of drug purchases by US pharmacies from wholesalers and manufacturers, from 2017 to 2021. Data were analyzed from January to May 2023. Exposure: Presence of a supply chain issue report to the US Food and Drug Administration or the American Society of Health-Systems Pharmacists (ASHP). Main Outcomes and Measures: The main outcome was drug shortage, defined as at least 33% decrease in units purchased within 6 months of a supply chain issue report. Random-effects logistic regression models compared the marginal odds of shortages for drugs with vs without reports. Interaction terms assessed heterogeneity prior to vs during the COVID-19 pandemic and by drug characteristics (formulation, age, essential medicine status, clinician- vs self-administered, sales volume, and number of manufacturers). Results: A total of 571 drugs exposed to 731 supply chain issue reports were matched to 7296 comparison medications with no reports. After adjusting for drug characteristics, 13.7% (95% CI, 10.4%-17.8%) of supply chain issue reports were associated with subsequent drug shortages vs 4.1% (95% CI, 3.6%-4.8%) of comparators (marginal odds ratio [mOR], 3.7 [95% CI, 2.6-5.1]). Shortages increased among both drugs with and without reports in February to April 2020 (34.2% of drugs with supply chain issue reports and 9.5% of comparison drugs; mOR, 4.9 [95% CI, 2.1-11.6]), and then decreased after May 2020 (9.8% of drugs with reports and 3.6% of comparison drugs; mOR, 2.9 [95% CI, 1.6-5.3]). Significant associations were identified by formulation (parenteral mOR, 1.9 [95% CI, 1.1-3.2] vs oral mOR, 5.4 [95% CI, 3.3-8.8]; P for interaction = .008), WHO essential medicine status (essential mOR, 2.2 [95% CI, 1.3-5.2] vs nonessential mOR, 4.6 [95% CI, 3.2-6.7]; P = .02), and for brand-name vs generic status (brand-name mOR, 8.1 [95% CI, 4.0-16.0] vs generic mOR, 2.4 [95% CI, 1.7-3.6]; P = .002). Conclusions and Relevance: In this national cross-sectional study, supply chain issues associated with drug shortages increased at the beginning of the COVID-19 pandemic. Ongoing policy work is needed to protect US drug supplies from future shocks and to prioritize clinically valuable drugs at greatest shortage risk.

Activity of cefiderocol and innovative ß-lactam/ß-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double ß-lactamases under high and low permeability conditions.

OBJECTIVES: To analyse the impact of the most clinically relevant ß-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. METHODS: We constructed 82 E. coli laboratory transformants expressing the main ß-lactamases circulating in Enterobacterales (70 expressing single ß-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. RESULTS: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of ß-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. CONCLUSIONS: Our findings highlight the promising activity that cefiderocol and new ß-lactam/ß-lactamase inhibitors have against recombinant E. coli strains expressing widespread ß-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.

Whole-genome characterisation of Escherichia coli isolates from patients with bacteraemia presenting with sepsis or septic shock in Spain: a multicentre cross-sectional study.

BACKGROUND: Escherichia coli is the most frequent cause of bloodstream infections (BSIs). About one-third of patients with BSIs due to E coli develop sepsis or shock. The objective of this study is to characterise the microbiological features of E coli blood isolates causing sepsis or septic shock to provide exploratory information for future diagnostic, preventive, or therapeutic interventions. METHODS: E coli blood isolates from a multicentre cross-sectional study of patients older than 14 years presenting with sepsis or septic shock (according to the Third International Consensus Definitions for Sepsis and Septic Shock criteria) from hospitals in Spain between Oct 4, 2016, and Oct 15, 2017, were studied by whole-genome sequencing. Phylogroups, sequence types (STs), serotype, FimH types, antimicrobial resistance (AMR) genes, pathogenicity islands, and virulence factors were identified. Susceptibility testing was performed by broth microdilution. The main outcome of this study was the characterisation of the E coli blood isolates in terms of population structure by phylogroups, groups (group 1: phylogroups B2, F, and G; group 2: A, B1, and C; group 3: D), and STs and distribution by geographical location and bloodstream infection source. Other outcomes were virulence score and prevalence of virulence-associated genes, pathogenicity islands, AMR, and AMR-associated genes. Frequencies were compared using χ² or Fisher's exact tests, and continuous variables using the Mann-Whitney test, with Bonferroni correction for multiple comparisons. FINDINGS: We analysed 224 isolates: 140 isolates (63%) were included in phylogenetic group 1, 52 (23%) in group 2, and 32 (14%) in group 3. 85 STs were identified, with four comprising 44% (n=98) of the isolates: ST131 (38 [17%]), ST73 (25 [11%]), ST69 (23 [10%]), and ST95 (12 [5%]). No significant differences in phylogroup or ST distribution were found according to geographical areas or source of bloodstream infection, except for ST95, which was more frequent in urinary tract infections than in other sources (11 [9%] of 116 vs 1 [1%] of 108, p=0·0045). Median virulence score was higher in group 1 (median 25·0 [IQR 20·5-29·0) than in group 2 (median 14·5 [9·0-20·0]; p<0·0001) and group 3 (median 21 [16·5-23·0]; p<0·0001); prevalence of several pathogenicity islands was higher in group 1. No significant differences were found between phylogenetic groups in proportions of resistance to antibiotics. ST73 had higher median virulence score (32 [IQR 29-35]) than the other predominant clones (median range 21-28). Some virulence genes and pathogenicity islands were significantly associated with each ST. ST131 isolates had higher prevalence of AMR and a higher proportion of AMR genes, notably blaCTX-M-15 and blaOXA-1. INTERPRETATION: In this exploratory study, the population structure of E coli causing sepsis or shock was similar to previous studies that included all bacteraemic isolates. Virulence genes, pathogenicity islands, and AMR genes were not randomly distributed among phylogroups or STs. These results provide a comprehensive characterisation of invasive E coli isolates causing severe response syndrome. Future studies are required to determine the contribution of these microbiological factors to severe clinical presentation and worse outcomes in patients with E coli bloodstream infection. FUNDING: Instituto de Salud Carlos III.

Effects of the valsartan recall on heart failure patients: A nationwide analysis.

BACKGROUND: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives. METHODS: We conducted a cohort study of Optum's de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups. RESULTS: Of the 87 130 adherent patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95% CI 0.96-1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95% CI 0.97-1.12). CONCLUSIONS: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system.

Net prices of new antiobesity medications.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP1s) are effective antiobesity drugs and the subject of intense debate around insurance coverage due to the large prevalence of obesity and overweight. The estimation of the budget impact associated with GLP1 insurance coverage requires estimates of GLP1 prices that account for manufacturer discounts. The authors applied a peer-reviewed method to estimate the net prices of GLP1s after manufacturer discounts. METHODS: The authors estimated manufacturer discounts for each product as the difference between the gross sales estimated at list price and manufacturer-reported revenue. From this difference, the authors subtracted discounts to government programs, including 340B, Medicaid, and the Medicare Part D coverage gap, and attributed the remaining amount to manufacturer discounts provided in the commercial market. RESULTS: Manufacturer discounts for GLP1s approved for obesity were estimated at 41%, which translated into net prices of $717 to $761 per month of supply. Manufacturer discounts for GLP1s approved for type 2 diabetes ranged from 54% to 59%, which translated into net prices of $312 to $469 per month of supply. CONCLUSIONS: The magnitude of manufacturer discounts underscores the need to consider net price information in studies that inform private and public payers' decision-making around coverage of GLP1s for obesity.