Addressing urgent priorities in antibiotic development: insights from WHO 2023 antibacterial clinical pipeline analyses.

Antimicrobial resistance continues to evolve and remains a leading cause of death worldwide, with children younger than 5 years being among those at the highest risk. Addressing antimicrobial resistance requires a comprehensive response, including infection prevention efforts, surveillance, stewardship, therapy appropriateness and access, and research and development. However, antimicrobial research and development is limited and lags behind the output of other fields, such as that of cancer or HIV research.

Multi-year analysis of the global preclinical antibacterial pipeline: trends and gaps.

Antimicrobial resistance (AMR) is a major global health threat estimated to have caused the deaths of 1.27 million people in 2019, which is more than HIV/AIDS and malaria deaths combined. AMR also has significant consequences on the global economy.

Impact of ambulatory care pharmacist intervention on 30-day readmission rates in high-risk transitions-of-care patients.

Background: Care transitions are a challenging and crucial point for many high-risk patients; errors in medication use can result in preventable hospital readmissions, which worsen patient outcomes and result in decreased reimbursement and increased expenses for health systems. Transitions of care (TOC) is an opportunity where pharmacists in the outpatient setting can prevent medication errors and decrease hospital readmissions.

Objective: The primary objective of this study was to evaluate the impact of pharmacist-conducted comprehensive medication reviews (CMRs) on 30-day hospital readmission rates.

Antigenic landscapes on pore-forming toxins reveal insights into specificity and cross-neutralization.

carries an exceptional repertoire of virulence factors that aid in immune evasion. Previous single-target approaches for -specific vaccines and monoclonal antibodies (mAbs) have failed in clinical trials due to the multitude of virulence factors released during infection. Emergence of antibiotic-resistant strains demands a multi-target approach involving neutralization of different, non-overlapping pathogenic factors.

Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed.

There is an urgent global need for new strategies and drugs to control and treat multidrug-resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes "traditional" and "nontraditional" antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens mycobacteria and Clostridioides difficile.

The CARB-X Portfolio of Nontraditional Antibacterial Products.

The growing prevalence of antibiotic-resistant bacterial pathogens and the lack of new medicines to treat the infections they cause remain a significant global threat. In recent years, this ongoing unmet need has encouraged more research groups to focus on the discovery and development of nontraditional antibacterial agents, ranging from anti-virulence strategies to bacteriophage and ways to modulate the microbiome. The Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) is a global nonprofit public-private partnership dedicated to accelerating antibacterial-related research.

A one health framework to estimate the cost of antimicrobial resistance.

Objectives/purpose: The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level.

A novel pre-clinical antibacterial pipeline database.

The clinical pipeline continues to be insufficient to contain antimicrobial resistance, and further investment and research is needed to ensure that a robust pipeline is built to treat the WHO priority pathogens list of antibiotic-resistant bacteria. To shed light further upstream on the preclinical pipeline the WHO has undertaken a review of the antibacterial preclinical pipeline and published the data of all identified projects in a publicly accessible database. The database captures 252 unique antibacterial agents in preclinical development being developed by 145 individual institutions, of which the majority are smaller biotech companies and academic institutions.

Narrow-Spectrum Antibacterial Agents-Benefits and Challenges.

The number of antibacterial agents in clinical and preclinical development possessing activity against a narrow spectrum of bacterial pathogens is increasing, with many of them being nontraditional products. The key value proposition hinges on sparing antibiotic use and curtailing the emergence of resistance, as well as preventing the destruction of a beneficial microbiome, versus the immediate need for effective treatment of an active infection with a high risk of mortality. The clinical use of a targeted spectrum agent, most likely in combination with a rapid and robust diagnostic test, is a commendable goal with significant healthcare benefits if executed correctly.

Innovation in Antimicrobial Resistance: The CARB-X Perspective.

The spread of drug-resistant bacterial pathogens has been recognized as one of the largest global threats to mankind. In order to continue to benefit from the advancement of modern medicine, new treatments, prevention, and diagnostic products are needed to satisfactorily treat or prevent infections. Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) is a global nonprofit public-private partnership dedicated to accelerating antibacterial-related research to tackle the rising threat of drug-resistant bacteria.

Population health model for pharmacist assessment and independent prescribing of statins in an ambulatory care setting.

Objective: This study aimed to evaluate the impact of a pharmacist population health initiative on the ability to increase the percentage of patients with atherosclerotic cardiovascular disease (ASCVD) who are on an appropriate statin.

Setting: Ten primary care clinics in Southwest Washington. The average payer mix across the included clinics is 47% Medicare, 26% commercial, 22% Medicaid, 2% self-pay, and 3% other.

Lack of Ability to Present Antigens on Major Histocompatibility Complex Class II Molecules Aggravates Atherosclerosis in ApoE Mice.

Background: Hypercholesterolemic mice lacking factors required for activation of CD4 T cells are characterized by reduced development of atherosclerosis. Consequently, it has been assumed that atherosclerosis involves loss of tolerance against modified self-antigens generated in response to hypercholesterolemia and that presentation of such antigens on major histocompatibility complex class II (MHCII) leads to activation of proatherogenic Th1 cells. In this study, we wanted to determine the role of antigen presentation on MHCII in atherosclerosis development.

Ceftaroline efficacy against high-MIC clinical Staphylococcus aureus isolates in an in vitro hollow-fibre infection model.

Objectives: The current CLSI and EUCAST clinical susceptible breakpoint for 600 mg q12h dosing of ceftaroline (active metabolite of ceftaroline fosamil) for Staphylococcus aureus is ≤1 mg/L. Efficacy data for S. aureus infections with ceftaroline MIC ≥2 mg/L are limited.

Identification of non-PBP2a resistance mechanisms in Staphylococcus aureus after serial passage with ceftaroline: involvement of other PBPs.

Objectives: Ceftaroline (the active metabolite of ceftaroline fosamil) is a cephalosporin that possesses activity against MRSA due to its differentiating high affinity for PBP2a. It is known that PBP2a sequence variations, including some outside of the transpeptidase-binding pocket, impact ceftaroline susceptibility and recent evidence suggests involvement of non-PBP2a mechanisms in ceftaroline resistance. This study evaluated the potential of ceftaroline to select for resistant Staphylococcus aureus clones during serial passage.

Structural and sequence analysis of class A β-lactamases with respect to avibactam inhibition: impact of Ω-loop variations.

Background: There exists a significant diversity among class A β-lactamases and the proliferation of these enzymes is a significant medical concern due to the ability of some members to efficiently hydrolyse both extended-spectrum cephalosporins and carbapenems. Avibactam is a novel non-β-lactam β-lactamase inhibitor that, in combination with ceftazidime, has recently obtained regulatory approval in the USA. Although avibactam is known to efficiently inhibit key class A enzymes, the diversity of this enzyme family warranted a more complete investigation to understand the breadth of the potential spectrum of inhibition.

Multi-center and multi-method evaluation of in vitro activities of ceftaroline against S. aureus.

This five-site study was performed to assess the reproducibility of ceftaroline MIC and disk results for Staphylococcus aureus. Three commercial broth microdilution, three gradient diffusion and ceftaroline 5μg disk diffusion methods were compared to a reference broth microdilution method against challenge isolates (n = 41) and isolates collected at four European sites (n = 30/site). For four MIC methods (Sensititre and three gradient diffusion methods), 99.

Plasma variation and reproducibility of oxidized LDL-cholesterol and low-grade inflammation biomarkers among participants of the Malmö Diet and Cancer cohort.

Context: Large epidemiological studies often collect non-fasting samples, although the reliability of biomarkers may be uncertain.

Objective: To explore the reliability and reproducibility of a single measurement of selected biomarkers in a sub-sample of the Malmö Diet and Cancer cohort.

Methods: We estimated single- and average-measures intraclass correlation coefficients (ICC) for oxidized (ox)-LDL, interleukin (IL)-1β, IL-6, IL-8 and TNF-α.

Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes.

Background And Purpose: Treatment with IgG against the malondialdehyde (MDA)-modified apolipoprotein B-100 epitope p45 reduces atherosclerosis in experimental models. This study investigated the association between p45 IgG autoantibodies and plaque inflammation in subjects with advanced cardiovascular disease.

Methods: Native and MDA-p45 IgG levels were analyzed by ELISA in 349 carotid endarterectomy patients.

Identification of Novel VEB β-Lactamase Enzymes and Their Impact on Avibactam Inhibition.

Ceftazidime-avibactam has activity against Pseudomonas aeruginosa and Enterobacteriaceae expressing numerous class A and class C β-lactamases, although the ability to inhibit many minor enzyme variants has not been established. Novel VEB class A β-lactamases were identified during characterization of surveillance isolates. The cloned novel VEB β-lactamases possessed an extended-spectrum β-lactamase phenotype and were inhibited by avibactam in a concentration-dependent manner.

Low Levels of Apolipoprotein B-100 Autoantibodies Are Associated With Increased Risk of Coronary Events.

Objective: Previous smaller studies have indicated inverse associations between autoantibodies to oxidized low-density lipoprotein epitopes, and cardiovascular disease. The present study investigated associations between autoantibodies against the apolipoprotein B-100 peptides p45 and p210, respectively, and risk of incident cardiovascular disease in a large population-based cohort.

Approach And Results: Apolipoprotein B-100 autoantibodies were analyzed by ELISA in a prospective study, including 5393 individuals (aged 46-68 years) belonging to the cardiovascular arm of the Malmö Diet and Cancer study with a follow-up time of >15 years.

Investigations into Improving Dewaterability at a Bio-P/Anaerobic Digestion Plant.

  Metropolitan Council Environmental Services has observed poorer than expected dewatering performance at its Empire Plant. This plant has both anaerobic digestion and enhanced biological phosphorus removal in its treatment train. A research program using pilot-scale anaerobic digesters investigated potential solutions to the plant's poor dewaterability.

In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolated in 2012 from Asia-Pacific Countries as Part of the AWARE Surveillance Program.

Ceftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). This investigation provides in vitro susceptibility data for ceftaroline against 1,971 S. aureus isolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program.

Potential of Staphylococcus aureus isolates carrying different PBP2a alleles to develop resistance to ceftaroline.

Objectives: Infections caused by MRSA continue to cause significant morbidity worldwide. Ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) is a cephalosporin that possesses activity against MRSA due to its having high affinity for PBP2a while maintaining activity against the other essential PBPs. PBP2a sequence variations, including some outside of the transpeptidase binding pocket, impact ceftaroline susceptibility.

Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914).

We tested the activity of ETX0914 against 187 Neisseria gonorrhoeae isolates from men with urethritis in Nanjing, China, in 2013. The MIC50, MIC90, and MIC range for ETX0914 were 0.03 μg/ml, 0.