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.

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.

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.

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.

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.

In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolates Collected in 2012 from Latin American Countries as Part of the AWARE Surveillance Program.

The in vitro activities of ceftaroline and comparators, using broth microdilution, were determined against 1,066 Staphylococcus aureus isolates from hospitalized patients. Seventeen medical centers from Latin American countries contributed isolates. Methicillin-resistant S.

Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors.

Insights into the mechanism of inhibition of novel bacterial topoisomerase inhibitors from characterization of resistant mutants of Staphylococcus aureus.

The type II topoisomerases DNA gyrase and topoisomerase IV are clinically validated bacterial targets that catalyze the modulation of DNA topology that is vital to DNA replication, repair, and decatenation. Increasing resistance to fluoroquinolones, which trap the topoisomerase-DNA complex, has led to significant efforts in the discovery of novel inhibitors of these targets. AZ6142 is a member of the class of novel bacterial topoisomerase inhibitors (NBTIs) that utilizes a distinct mechanism to trap the protein-DNA complex.

Molecular characterization of MRSA isolates bracketing the current EUCAST ceftaroline-susceptible breakpoint for Staphylococcus aureus: the role of PBP2a in the activity of ceftaroline.

Objectives: The objectives of this study were to characterize contemporary MRSA isolates and understand the prevalence and impact of sequence variability in PBP2a on ceftaroline susceptibility.

Methods: A total of 184 MRSA isolates collected from 28 countries were collected and characterized.

Results: WT PBP2a proteins were found in MRSA distributed evenly over the ceftaroline MIC range of 0.

Selection and molecular characterization of ceftazidime/avibactam-resistant mutants in Pseudomonas aeruginosa strains containing derepressed AmpC.

Objectives: Pseudomonas aeruginosa is an important nosocomial pathogen that can cause a wide range of infections resulting in significant morbidity and mortality. Avibactam, a novel non-β-lactam β-lactamase inhibitor, is being developed in combination with ceftazidime and has the potential to be a valuable addition to the treatment options for the infectious diseases practitioner. We compared the frequency of resistance development to ceftazidime/avibactam in three P.