Tackling the threat of antimicrobial resistance in neonates and children: outcomes from the first WHO-convened Paediatric Drug Optimisation exercise for antibiotics.

Children and neonates are highly vulnerable to the impact of antimicrobial resistance. Substantial barriers are faced in relation to research and development of antibacterial agents for use in neonates, children, and adolescents aged yonger than 19 years, and focusing finite resources on the most appropriate agents for development and paediatric optimisation is urgently needed. In November and December, 2022, following the successes of previous similar disease-focused exercises, WHO convened the first Paediatric Drug Optimisation (PADO) exercise for antibiotics, aiming to provide a shortlist of antibiotics to be prioritised for paediatric research and development, especially for use in regions with the highest burden of disease attributable to serious bacterial infection. A range of antibiotics with either existing license for children or in clinical development in adults but with little paediatric data were considered, and PADO priority and PADO watch lists were formulated. This Review provides the background and overview of the exercise processes and its outcomes as well as a concise review of the literature supporting decision making. Follow-up actions to implement the outcomes from the PADO for antibiotics process are also summarised. This Review highlights the major beneficial influence the collaborative PADO process can have, both for therapeutic drug class and disease-specific themes, in uniting efforts to ensure children have access to essential medicines across the world.

Impact of climate change and natural disasters on fungal infections.

The effects of climate change and natural disasters on fungal pathogens and the risks for fungal diseases remain incompletely understood. In this literature review, we examined how fungi are adapting to an increase in the Earth's temperature and are becoming more thermotolerant, which is enhancing fungal fitness and virulence. Climate change is creating conditions conducive to the emergence of new fungal pathogens and is priming fungi to adapt to previously inhospitable environments, such as polluted habitats and urban areas, leading to the geographical spread of some fungi to traditionally non-endemic areas. Climate change is also contributing to increases in the frequency and severity of natural disasters, which can trigger outbreaks of fungal diseases and increase the spread of fungal pathogens. The populations mostly affected are the socially vulnerable. More awareness, research, funding, and policies on the part of key stakeholders are needed to mitigate the effects of climate change and disaster-related fungal diseases.

Defining access without excess: expanding appropriate use of antibiotics targeting multidrug-resistant organisms.

Antimicrobial resistance remains a significant global public health threat. Although development of novel antibiotics can be challenging, several new antibiotics with improved activity against multidrug-resistant Gram-negative organisms have recently been commercialised. Expanding access to these antibiotics is a global public health priority that should be coupled with improving access to quality diagnostics, health care with adequately trained professionals, and functional antimicrobial stewardship programmes. This comprehensive approach is essential to ensure responsible use of these new antibiotics.

Social determinants of health as drivers of fungal disease.

Disparities in social determinants of health (SDOH) play a significant role in causing health inequities globally. The physical environment, including housing and workplace environment, can increase the prevalence and spread of fungal infections. A number of professions are associated with increased fungal infection risk and are associated with low pay, which may be linked to crowded and sub-optimal living conditions, exposure to fungal organisms, lack of access to quality health care, and risk for fungal infection. Those involved and displaced from areas of armed conflict have an increased risk of invasive fungal infections. Lastly, a number of fungal plant pathogens already threaten food security, which will become more problematic with global climate change. Taken together, disparities in SDOH are associated with increased risk for contracting fungal infections. More emphasis needs to be placed on systematic approaches to better understand the impact and reducing the health inequities associated with these disparities.

HIV and fungal priority pathogens.

The burden of invasive fungal infections associated with opportunistic fungal pathogens is a persistent challenge, particularly among people with advanced HIV disease. In October, 2022, WHO published the Fungal Priority Pathogens List (FPPL)-the first global effort to systematically prioritise fungal pathogens. Of the 19 pathogens in the WHO FPPL, four opportunistic pathogens in particular cause invasive diseases in people living with HIV: Cryptococcus neoformans, Histoplasma spp, Pneumocystis jirovecii, and Talaromyces marneffei. These four fungal pathogens are major causes of illness and death in people with advanced HIV and overwhelmingly affect those in low-income and middle-income countries. Access to diagnostics, improved surveillance, targeted support for innovation, and an enhanced public health focus on these diseases are needed in the effort to reduce HIV-associated deaths.

The role of bacterial vaccines in the fight against antimicrobial resistance: an analysis of the preclinical and clinical development pipeline.

Vaccines can be highly effective tools in combating antimicrobial resistance as they reduce infections caused by antibiotic-resistant bacteria and antibiotic consumption associated with disease. This Review looks at vaccine candidates that are in development against pathogens on the 2017 WHO bacterial priority pathogen list, in addition to Clostridioides difficile and Mycobacterium tuberculosis. There were 94 active preclinical vaccine candidates and 61 active development vaccine candidates. We classified the included pathogens into the following four groups: Group A consists of pathogens for which vaccines already exist-ie, Salmonella enterica serotype Typhi, Streptococcus pneumoniae, Haemophilus influenzae type b, and M tuberculosis. Group B consists of pathogens with vaccines in advanced clinical development-ie, extra-intestinal pathogenic Escherichia coli, Salmonella enterica serotype Paratyphi A, Neisseria gonorrhoeae, and C difficile. Group C consists of pathogens with vaccines in early phases of clinical development-ie, enterotoxigenic E coli, Klebsiella pneumoniae, non-typhoidal Salmonella, Shigella spp, and Campylobacter spp. Finally, group D includes pathogens with either no candidates in clinical development or low development feasibility-ie, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Helicobacter pylori, Enterococcus faecium, and Enterobacter spp. Vaccines are already important tools in reducing antimicrobial resistance and future development will provide further opportunities to optimise the use of vaccines against resistance.

The approach of World Health Organization to articulate the role and assure impact of vaccines against antimicrobial resistance.

Antimicrobial resistance (AMR) is a growing global problem and there were an estimated 4.95 million deaths associated with bacterial AMR worldwide in 2019. Vaccines can impact AMR by preventing infections and reducing the need for antibiotics which will inadvertently slow the emergence of AMR. Effective infection prevention and control (IPC) has been identified as the cornerstone action to combat AMR by the World Health Assembly and the Global Action plan on AMR. Similarly, the Immunization Agenda 2030 highlights vaccines as critical tools to combat AMR. This article summarizes the strategy of the World Health Organization to understand, articulate and communicate the important role of vaccines in countering AMR. The work is organized around developing a strategy, understanding the pipeline of vaccines in development, articulating the value of vaccines against AMR, and assuring sustainable impact of vaccines at a country level to combat AMR.

The WHO essential medicines list AWaRe book: from a list to a quality improvement system.

Antibiotics are often prescribed inappropriately, either when they are not necessary or with an unnecessarily broad spectrum of activity. AWaRe (AccessWatchReserve) is a system developed by WHO to classify antibiotics based on their spectrum of activity and potential for favouring the development of antibiotic resistance (Access: narrow spectrum/low potential for resistance; Watch: broader spectrum/higher potential for resistance; Reserve: last resort antibiotics to use very selectively). The WHO target is that by 2023, at least 60% of prescribed antibiotics globally should be from the Access category. The WHO AWaRe Book aims to improve empiric antibiotic prescribing by providing simple guidance for common infections based on the principles of AWaRe in alignment with the Model Lists of Essential Medicines for adults and children.

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. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 nontraditional), with 28 in phase 1, 32 in phase 2, 12 in phase 3, and 4 under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) were against mycobacteria, 15 (20%) were against C. difficile, and 4 (5%) were nontraditional agents with broad-spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores, and 4 of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical-priority pathogens. We believe that future antibacterial research and development (R&D) should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

Antibiotics and antimicrobial resistance in the COVID-19 era: Perspective from resource-limited settings.

The dissemination of COVID-19 around the globe has been followed by an increased consumption of antibiotics. This is related to the concern for bacterial superinfection in COVID-19 patients. The identification of bacterial pathogens is challenging in low and middle income countries (LMIC), as there are no readily-available and cost-effective clinical or biological markers that can effectively discriminate between bacterial and viral infections. Fortunately, faced with the threat of COVID-19 spread, there has been a growing awareness of the importance of antimicrobial stewardship programs, as well as infection prevention and control measures that could help reduce the microbial load and hence circulation of pathogens, with a reduction in dissemination of antimicrobial resistance. These measures should be improved particularly in developing countries. Studies need to be conducted to evaluate the worldwide evolution of antimicrobial resistance during the COVID-19 pandemic, because pathogens do not respect borders. This issue takes on even greater importance in developing countries, where data on resistance patterns are scarce, conditions for infectious pathogen transmission are optimal, and treatment resources are suboptimal.

Characterizing Shigella species distribution and antimicrobial susceptibility to ciprofloxacin and nalidixic acid in Latin America between 2000-2015.

BACKGROUND: Shigellosis is the second leading cause of diarrheal death globally. The global burden has been complicated by the emergence of Shigella strains resistant to first line antibiotic treatments such as ciprofloxacin. This study aims to describe the epidemiologic distribution of the most common Shigella species, and their antimicrobial susceptibility patterns to ciprofloxacin and nalidixic acid (NA) in Latin America. METHODS: Laboratory data from 19 countries were obtained through the Latin American Network for Antimicrobial Resistance Surveillance (ReLAVRA) from 2000-2015. The Clinical Laboratory Standards Institute reduced susceptibility breakpoints for Enterobacteriaceae was used to interpret the disc diffusion tests for Shigella susceptibility to ciprofloxacin and NA. Negative binominal regression was used to analyze longitudinal trends of Shigella isolates antimicrobial susceptibility. RESULTS: 79,548 Shigella isolates were tested and reported between 2000-2015. The most common isolated species were S. flexneri (49%), and S. sonnei (28%). There was a steady increase in the proportion of S. sonnei isolates within the region(p<0.001). The average annual percentage increase (AAPI) in nonsusceptibility was 18.4% (p<0.001) for ciprofloxacin (baseline = 0.3); and 13.2%(p<0.001) for NA (baseline = 3). AAPI nonsusceptibility to ciprofloxacin was 13.3% for S. flexneri (p<0.04); and 39.9% for S. sonnei (p<0.001). Honduras, Dominican Republic, Venezuela, and Chile reported the highest increase in nonsusceptibility to ciprofloxacin among all Shigella isolates. CONCLUSION: There is an increasing trend in Shigella nonsusceptibility to ciprofloxacin and NA, including among the most common shigella species, in Latin America. This rise of nonsusceptibility among Shigella species to commonly used treatments such as ciprofloxacin is alarming and threatens the control and management of this currently treatable infection. Improved data quality, collection and reporting is needed in Latin America to respond effectively to the rising trends observed. This includes the need for quality isolate level epidemiological data; molecular data, and data on antibiotic consumption and use.

["One health" approach in the actions to address antimicrobial resistance from a latin american standpoint]. / Enfoque de una salud en las acciones para enfrentar la resistencia a los antimicrobianos desde una óptica latinoamericana.

Antimicrobial resistance is a complex epidemiology problem worldwide which calls for a wide and integrated approach such as "One Health." Resistant organisms are present in humans, animals, food, and the environment, and the main impeller of this resistance is the use of antimicrobial agents. The occurrence and propagation of antimicrobial resistance continue incessantly in the world, leaving devastating economic and health consequences behind. In 2015, the WHO, in collaboration with key partners such as the FAO and the OIE, developed the World Action Plan in Antimicrobial Resistance, under the perspective of "One Health." This Plan was endorsed by several countries and seeks collaboration for the prevention and control of antimicrobial resistance. This article aims at explaining the scope of the "One Health" approach within the context of antimicrobial resistance, the reason behind its adoption and what is expected from it. One of the main conclusions is the significant lack of knowledge on the selection and propagation of resistant organisms in the environment, with an emphasis on the threats and risks that this represents to human and animal health. Efforts need to be strengthened in order to better define the risks, design interventions, and measure its impact on antimicrobial resistance.

La resistencia a los antimicrobianos es un problema global de epidemiología compleja, adecuado para un enfoque amplio e integrado de «Una Salud¼. Existen organismos resistentes en humanos, animales, alimentos y el medio ambiente, y el principal impulsor de esta resistencia es el uso de antimicrobianos. La aparición y propagación de la resistencia a los antimicrobianos continúa sin cesar en todo el mundo, dejando devastadores resultados de salud y económicos a su paso. En el 2015, la OMS, en colaboración con socios clave como la FAO y la OIE, desarrolló el Plan de Acción Mundial en Resistencia a los Antimicrobianos, bajo la perspectiva de «Una Salud¼. Este Plan fue endosado por los países y busca la colaboración para la prevención y control de la resistencia a los antimicrobianos. En este artículo, se pretende explicar el alcance del enfoque «Una Salud¼ en el contexto de la resistencia a los antimicrobianos, por qué se ha adoptado y qué se espera lograr con ello. Una de las conclusiones principales es la gran falta de conocimiento sobre la selección y propagación de organismos resistentes en el medio ambiente, con énfasis en las amenazas y riesgos que esto representa para la salud humana y animal. Se han de intensificar los esfuerzos para mejor definir los riesgos, diseñar las intervenciones y medir su impacto en la resistencia a los antimicrobianos.

Enfoque de una salud en las acciones para enfrentar la resistencia a los antimicrobianos desde una óptica latinoamericana / "One health" approach in the actions to address antimicrobial resistance from a latin american standpoint

RESUMEN La resistencia a los antimicrobianos es un problema global de epidemiología compleja, adecuado para un enfoque amplio e integrado de «Una Salud¼. Existen organismos resistentes en humanos, animales, alimentos y el medio ambiente, y el principal impulsor de esta resistencia es el uso de antimicrobianos. La aparición y propagación de la resistencia a los antimicrobianos continúa sin cesar en todo el mundo, dejando devastadores resultados de salud y económicos a su paso. En el 2015, la OMS, en colaboración con socios clave como la FAO y la OIE, desarrolló el Plan de Acción Mundial en Resistencia a los Antimicrobianos, bajo la perspectiva de «Una Salud¼. Este Plan fue endosado por los países y busca la colaboración para la prevención y control de la resistencia a los antimicrobianos. En este artículo, se pretende explicar el alcance del enfoque «Una Salud¼ en el contexto de la resistencia a los antimicrobianos, por qué se ha adoptado y qué se espera lograr con ello. Una de las conclusiones principales es la gran falta de conocimiento sobre la selección y propagación de organismos resistentes en el medio ambiente, con énfasis en las amenazas y riesgos que esto representa para la salud humana y animal. Se han de intensificar los esfuerzos para mejor definir los riesgos, diseñar las intervenciones y medir su impacto en la resistencia a los antimicrobianos.

ABSTRACT Antimicrobial resistance is a complex epidemiology problem worldwide which calls for a wide and integrated approach such as "One Health." Resistant organisms are present in humans, animals, food, and the environment, and the main impeller of this resistance is the use of antimicrobial agents. The occurrence and propagation of antimicrobial resistance continue incessantly in the world, leaving devastating economic and health consequences behind. In 2015, the WHO, in collaboration with key partners such as the FAO and the OIE, developed the World Action Plan in Antimicrobial Resistance, under the perspective of "One Health." This Plan was endorsed by several countries and seeks collaboration for the prevention and control of antimicrobial resistance. This article aims at explaining the scope of the "One Health" approach within the context of antimicrobial resistance, the reason behind its adoption and what is expected from it. One of the main conclusions is the significant lack of knowledge on the selection and propagation of resistant organisms in the environment, with an emphasis on the threats and risks that this represents to human and animal health. Efforts need to be strengthened in order to better define the risks, design interventions, and measure its impact on antimicrobial resistance.