Antimicrobial resistance surveillance system mapping in different countries

Introduction

In the last few decades extensive use of antibiotics has resulted in rising cases of antimicrobial resistance (AMR) against various organisms. From narrow-spectrum antibiotics, people shifted to broad-spectrum antibiotics, which eventually increased the high resistance rates. Multidrug-resistant (MDR) bacterial infections are rapidly emerging and spreading over the world, posing a severe threat to global healthcare. Carbapenem-resistant Enterobacteriaceae (CRE), a type of gram-negative bacteria that has resisted all or virtually all current antibiotics, is one cause for concern. Likewise, various other antibiotics are also becoming resistant against the microorganisms causing immense threat among the population. This global threat comprises of both commensal and pathogenic bacteria. The similarities between human and animal diseases, as well as the interactions between animals and humans who come into contact with them, have long been recognized. Human and veterinary medicine diverged in the twentieth century. During the same time span, our understanding of infectious diseases and antibiotics grew dramatically. The necessity for partnerships between human health and veterinary sectors to prevent and control zoonotic illnesses and antibiotic resistance grew in the second half of the twentieth century. The notion of ecosystem health developed toward the end of the twentieth century, extending the integration and collaboration of human and animal medicine to the environment. Later on, the phrase “One Health” was coined to describe a holistic approach to improving human, animal, and environmental health through multidisciplinary cooperation and communication. Several global plans have been established to combat the AMR epidemic, including the World Health Organization’s (WHO) Global Action Plan (GAP), the new European One Health Action Plan against AMR, and the Central Asian and Eastern European Surveillance of Antimicrobial Resistance (CAESAR) network (1). Surveillance and monitoring systems for Antimicrobial Usage (AMU) and AMR in humans and animals are critical for assessing and controlling global trends in antimicrobial use and antimicrobial susceptibility patterns of bacteria in various populations. In the context of a One Health strategy, zoonotic and indicator microorganisms are especially important. A strategic framework for reducing infectious disease risks at the animal-human ecosystem interface was published in 2008, adopting and promoting the One Health concept. The One Health Approach has been supported and implemented by a wide number of national and international institutes since 2008. Research on the human-animal environment interaction is critical to supporting the call for a One Health Approach to AMR and infectious illnesses. Furthermore, training and extension initiatives are critical for promoting the One Health idea and facilitating its application among various stakeholders (2,3). Several governments and international organizations have now included a One Health Approach in the AMR action plans. Improvements in antimicrobial use, better regulation and policy, improved surveillance, stewardship, infection control, sanitation, animal husbandry, and identifying antimicrobial alternatives are all necessary efforts. This report summarizes research and educational activity in the field of One Health in Western Europe, with an emphasis on infectious diseases. It might act as a springboard for future collaborations and projects.

Materials and methods

Data sources

We conducted a database study for collecting major characteristics of surveillance and monitoring systems on antimicrobial use and AMR in cattle and people, as well as AMR systems in food, in this publication. Countries such as Spain, Germany, France, the Netherlands, Norway, and the United Kingdom were considered for this project. The literature searches in recent times have been carried out to understand and collect the data from different gray reports and other AMR databases. The database study has been conducted by searching the terms “Antimicrobial Resistance,” “Antibiotic Usage,” “One Health Approach” on PubMed and desired research papers or data sheets annually published by different agencies are studied for collective data required for this research article. Additionally, information about One Health Approach in these countries was also investigated for obtaining the results. One Health policy publications issued by international organizations and countries also provided background information on the One Health program and European One Health projects. Moreover, Google research on One Health with its associated activities and trainings among these countries was conducted for acquiring more relevant outcomes. Alternative antibiotics for resolving the issue of AMR were also researched which focuses on better solution for AMR and antimicrobial usage. One of the renowned projects also known as ARDIG (Antimicrobial Resistance Dynamics the Influence of Geographic origin) together collects and gathers data related to AMR and usage of antimicrobials from both human and veterinary sectors. The stipulated graph depicts the predicted deaths that will be increasing for the usage of antibiotics globally by the year 2050 (Fig. 1) (4). This helps us to portray the comparison study of all the data collected for different countries along with the Asian countries. In addition, all the surveillance systems for monitoring AMR in different countries of Europe have been explained thoroughly in this article. The primary reason for tracking the reports of European countries is because One Health has gained a lot of traction throughout Europe. The One Health strategy is currently being promoted in Europe mostly in regard to AMR. Many nations have adopted the One Health concept in their anti-AMR policies, and funding opportunities for AMR research have considerably increased. In the areas of zoonotic diseases and One Health, the number of national and international multidisciplinary research networks is growing (1,5,6).

Results

The accomplished research revealed that various surveillance systems are actively working to follow a trail of the upcoming situation of AMR and antimicrobial consumption by humans as well as animals. These surveillance systems of European countries are jointly contributing in statistically analyzing the rising situation of AMR and the prominent measures taken by different organizations for implementing One Health Approach. Moreover, various training institutes and alternative measures for preventing AMR are firmly encouraged in these six European countries along with Taiwan and India. Data of AMR solely do not arise from consuming antibiotics. There are multiple more aspects such as food habits of the humans, food chains maintained by the healthy animals, and the environment that together exhibit the importance of surveillance systems for AMR as these features put up the AMR issue topmost. The EFSA is in charge of communication on food chain concerns. Annually, the EFSA and the European Centre for Disease Prevention and Control (ECDC) collect AMR data on humans, food, and healthy animals from EU States and some affiliated countries (5). The European Union summary report on AMR in zoonotic and indicator bacteria from humans, animals, and food is prepared and published by the EFSA. Also, some nongovernmental organizations such as European Animal Health Study Centre (CEESA) are also contributing by researching about AMR and forming relevant systems to perform the activities efficiently (6). Precisely, the organization is working in monitoring the antimicrobial susceptibility of the bacterial pathogens that have the potential of causing diseases among the animals along with the foodborne pathogens in animal’s food. These organizations are not the only aide for this surveillance system; a prime system also called as the European Antimicrobial Resistance Surveillance Network (EARS-Net) mainly helps in the surveillance of AMR data. This is an AMR surveillance network established in compliance with European Union and European Economic Area legislation. The ECDC collects AMR data from EU States through EARS-Net and publishes the annual EARS-Net report. On that account it is extremely crucial to compare the percentages of antibiotic usage and AMR, which will help in displaying the numbers accurately acquired from different organizations and relevant measures will be implemented for better solution. Similarly, acknowledging this, two joint interagency reports for antibiotic consumption and the analysis of AMR were published that clearly demonstrate the effects of using extensive antibiotics on humans and animals and the data were compared to AMR reports for better understanding. This report is jointly published by the European Medicines Agency (EMA), the EFSA, and the ECDC. The ECDC and EARS-Net require other platforms to jointly work for this (Fig. 2). Every country from Europe has its own surveillance system for AMR that they follow, and prepared reports are further provided to EFSA. The AMR surveillance system is developed distinctly for humans and livestock (1).

Different systems of the country contribute in forming the reports, which are eventually published by EFSA or ECDC (Fig. 3).

Similarly, AMR surveillance system for humans is also analyzed by different organizations formed in these six European countries. Figure 4 depicts the organizations that are being established for keeping the record of the AMR surveillance (6).

Tables I and II give details about all the aforementioned surveillance system followed by the distinct countries along with the features and roles they perform (1,7).

Humans and animals are exposed to AMR from their food habits. Thus, a surveillance system was set up especially for the food that is being consumed by both animals and humans. A thorough monitoring of the food consumed has the possibility of getting exposed to new pathogenic organisms, which could be a probable reason for pandemic, endemic, and epidemic. Again, some of the organizations similar to humans and livestock are formed for keeping the track of rising AMR cases from food habits (Fig. 5) (1).

All the aforementioned the organizations report their AMR data to EFSA but on the other hand, there are some organizations that do not report their AMR data to EFSA (Tab. III). The details of all these organizations contributing to different countries are described further (1).

Reported microorganisms accountable for AMR in Europe

Discussing about the surveillance systems available to control the AMR and antimicrobial usage will not help the population be aware about the pathogenic disease-causing microorganisms accurately. Therefore, it is very important to understand the pathogens responsible for causing AMR also with the antimicrobials that are extensively used. EARS-Net received data from 29 countries for all eight bacterial species under observation (E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter species, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium). E. coli was the most commonly reported bacterial species (44.2%), followed by S. aureus (20.6%), K. pneumoniae (11.3%), E. faecalis (6.8%), P. aeruginosa (5.6%), S. pneumoniae (5.3%), E. faecium (4.5%), and Acinetobacter species (4.5%) (Fig. 6) (12). In 2019, more than half of E. coli isolates reported to EARS-Net were resistant to at least one antimicrobial group under surveillance, and more than a third of K. pneumoniae isolates were resistant to multiple antimicrobial groups. In general, resistance percentages in K. pneumoniae were higher than in E. coli. While carbapenem resistance was uncommon in E. coli, carbapenem resistance rates in K. pneumoniae were reported to be more than 10% in numerous countries. Carbapenem resistance was also found in larger percentages in P. aeruginosa and Acinetobacter species than in K. pneumoniae. The increase in the percentage of vancomycin-resistant E. faecium isolates in the EU/EEA from 10.5% in 2015 to 18.3% in 2019 is a cause for concern. The results of antimicrobial susceptibility testing (AST) from invasive (blood or cerebrospinal fluid) isolates of eight bacterial species are provided in this article. E. coli, K. pneumoniae, P. aeruginosa, Acinetobacter species, S. pneumoniae, S. aureus, E. faecalis, and E. faecium are all important bacteria for public health in Europe. In 2019, the estimated national population coverage of data provided to EARS-Net ranged from 11% to 100%, with more than a third of the nations reporting a population coverage of 80% or above (12).

Surveillance system	Country	Hosts
GERM-VET	Germany	Livestock
RESAPATH	France	Animals
APHA-VET PATHOGENS	United Kingdom	Diseased animals
SRUC	United Kingdom	Animals
PEG	Germany	Human pathogens
ARMIN	Germany	Humans
BARDa	Germany	Humans
ICU-KISS, OP-KISS, SARI-KISS, MRSA-KISS	Germany	Human pathogens
BSAC	United Kingdom	Humans
BMR-RAISINS	France	Human pathogens

Escherichia coli

In Europe, E. coli is a common cause of bloodstream infection. Infections caused by antimicrobial-resistant E. coli account for the majority of AMR cases in the EU. The percentages of AMR reported in 2019 were substantially higher than in 2002, underlining the need for more antimicrobial stewardship and infection prevention and control activities. According to the latest data from the European Surveillance of Antimicrobial Consumption Network (ESAC-Net), there are large inter-country variations in the use of broad-spectrum antimicrobials, indicating a need for increased antimicrobial stewardship and the potential for further antimicrobial consumption reductions (13).

Pseudomonas aeruginosa

Although P. aeruginosa is naturally resistant to a wide range of antimicrobials, acquired resistance complicates the treatment of P. aeruginosa infections. Because P. aeruginosa is still one of the most common causes of healthcare-associated illness in Europe, the public health consequences of AMR in P. aeruginosa should not be overlooked (12).

Klebsiella pneumoniae

Due to K. pneumoniae’s great resistance, the European Union is currently dealing with a significant issue. Although carbapenem resistance has increased more than seven-fold since 2006, it has been more moderate in the last 5 years than in earlier eras. The WHO believes that novel drugs targeting third-generation cephalosporin- and carbapenem-resistant Enterobacterales, such as K. pneumoniae and E. coli, are urgently needed.

Staphylococcus aureus

Many nations have created and implemented national methicillin-resistant Staphylococcus aureus (MRSA) prevention recommendations and guidance documents, emphasizing on enhanced infection prevention and control as well as sensible antibiotic usage. Despite this progress, MRSA remains a significant pathogen in Europe. S. aureus is one of the most frequent bacteria that causes bloodstream infections, with a significant morbidity and fatality rate. MRSA surveillance in animals and food is currently voluntary and only carried out in a few countries. This monitoring, however, reveals an ever-changing situation, including the detection of livestock-associated MRSA (LA-MRSA), healthcare-associated MRSA, and community-associated MRSA from companion animals and/or livestock. LA-MRSA has recently received increased attention as a zoonotic risk, particularly for those who work in close proximity to livestock.

Acinetobacter species

Acinetobacter species have the widest inter-country range in resistance percentages of any bacterial species under EARS-Net surveillance. Depending on the reporting country, the percentage of isolates resistant to at least one of the antimicrobial groups under surveillance (fluoroquinolones, aminoglycosides, or carbapenems) ranged from 0% to 95.8% in 2019. Because Acinetobacter species is naturally resistant to many antimicrobial agents, acquired resistance complicates treatment of Acinetobacter species infections. MDR Acinetobacter species are a problem in the healthcare environment because they can survive for long periods of time in the environment and are notoriously difficult to eradicate once established.

Streptococcus pneumoniae

In addition to EARS-Net, the enhanced surveillance program for invasive pneumococcal disease (IPD), which is also supervised by ECDC, collects additional data on IPD cases from reference laboratories across the EU/EEA. The frequency of resistance to penicillin and erythromycin grew somewhat in all countries that consistently supplied antimicrobial susceptibility data, according to data from this surveillance project (13).

Enterococcus faecalis and Enterococcus faecium

There are grounds for concern that E. faecium is fast and constantly increasing in the percentage of vancomycin resistance in the EU. The ECDC study on AMR’s health burden estimated that vancomycin-resistant enterococci (VRE) infections and fatalities virtually doubled. A large issue for infection prevention and an important cause for dietary-related illnesses remain high levels of antimicrobial-resistant enterococci. In addition to being difficult to cure infections caused by resistant strains, enterococci are easily spread in medical settings (12).

One Health Approach regulating AMR in Taiwan

Taiwan’s Centers for Disease Control (CDC) implemented the National Antimicrobial Stewardship Program; established multi-channel monitoring of MDR organisms, hospital accreditation, and hospital infection control inspections related to antimicrobial stewardship; coordinated infection control interventions; and carried out antimicrobial control interventions in response to the growing threat posed by AMR. Taiwan CDC also proactively establishes relevant guidelines, e-learning materials, manual hygiene, and antimicrobial awareness campaigns to encourage everyone to reduce this condition. Main objectives are:

Enhanced surveillance and control of carbapenem-resistant Enterobacteriaceae of antimicrobial-resistant pathogens;

Accredit and control hospital infections;

Hospital inspections, the antimicrobial stewardship of all hospitals, are necessary or encouraged;

Offer a number of e-learning courses to improve the understanding and consciousness of health workers on antimicrobial stewardship;

Conduct national public and health awareness-raising campaigns;

Cooperate on the fight against AMR with human and animal health sectors (23).

Thus, a comparative study has highlighted the fact that European countries as well as Asian countries such as India and Taiwan are equally contributing in building various agencies and organizations for combating AMR by implementing various policies and many other surveillance systems, which has actively increased the implementation of One Health Approach. In addition, after European countries, Taiwan has successfully accomplished many of their objectives which have helped the country in fighting against the AMR. Some of the above-mentioned strategies to prevent AMR are broadly explained (Figs. 8 and 9) (24). The mapping of the surveillance system set up for AMR in Taiwan is described further (Fig. 8) (25).

Discussion

This article provides an overview of various surveillance systems that are formed only to keep a track on the upcoming situation of AMR and the consumption of antimicrobials by humans as well as animals. The article does not provide all the details required to monitor the AMR issue but firmly allows the readers to get acknowledged with the broad information about the AMR across the six countries of Europe along with a comparative study between Taiwan and India. There are also a lot of debates on the themes of research covered by the term “One Health.” Any field of research, including anthropology, sociology, pedagogies, or comparative medicine, that may contribute to human, animal, or ecosystem health can be “One Health.” Failure to treat certain infections with currently available antibiotics is a concern for biomedicine. Phage therapy as an alternative therapy against bacterial infections has been extensively investigated. Although various challenges exist, bacteriophages treatment could be used in the future to replace antimicrobial agents with pathogens that are drug-resistant. The technique is now becoming popular as photographs are omnipresent, host-specific and harmless and can be administered with food orally. Antibiotic protein in target bacteria is developed for the delivery of recombinant phages. Topical treatment for open wounds or systemic infections may be performed intravenously. However, phage therapy gives rise to some serious concerns. The main thing about the host bacterium is its fine specificity. This prevents their use for acute infections as empirical therapy. The basis for their investigation was bacteriophageal lysins, the extremely specific peptidoglycan hydrolases, and was also referred to as enzybiotics. Incorporated lysins represent a new therapy form that is powerful and readily available to fight AMR as MDR diseases are becoming increasingly common threats (26,27). With the emerging crisis of AMR, vaccine treatments are seen as a possible solution by health authorities, healthcare providers, and drug developers. The biomolecules that boost the host immune system and give immunity against infectious agents are immunotherapeutic. Developments in the new technology of recombinant vaccines have been essential for reducing the use of different antibiotics for primary and secondary bacterial infection. One of the most important ways to prevent infections continues to be vaccines. Increasing the internal immune system is the advantage of immunotherapeutic agents (24). The CRISPR case is a distinguishing adaptive immune feature in archaea and bacteria, which offers protection against invasively invading bacteriophages and provides a regularly cross-sectional breast repeat. Short bacteriophages or plasmids known as spacers are inserted as a CRISPR array into the bacterial genome; the Cas proteins use guide RNAs from spacers to target the invading nucleic acid with the same sequence. Phagemids from CRISPR-Cas9 could kill certain in vivo bacteria. CRISPR Nanosized Compounds can target the Mec-A gene that is involved in the MRSA effectively (28). Mesenchymal stem cells (MSCs) have been intensively investigated for a variety of chronic diseases over several decades in order to develop a safe and promising therapeutical product. MSCs show promising skills in promoting immunomodulation, tissue cure and excessive inflammation control. Recently, human MSCs have been shown to synthesize antimicrobial peptide (AMP) factors that eradicate bacteria through several mechanisms including an inhibition of bacterial cell wall synthesis. Nonbacterial effects of MSCs (HUCMSCs) on drug-resistant clinical pathogens like E. coli, S. aureus, and K. pneumoniae have been detected (29). A number of names known as fecal microbiota transplantation are known as fecal bacteriotherapy. The Fecal Microbiota Transplantation (FMT) pro­cess involves the transplantation, using various routes, including enema, nasogastric, nasoduodenal and colonoscopy, of a fecal suspension of commensal bacteria by a healthy individual donor into the intestinal lumen of the recipients. Clinical trials have found an automotive FMT (aFMT) in antibiotic-disrupted human patients that is better than probiotic therapy and that has induced a fast and almost complete recovery of gastrointestinal microbiota (30). Nanoparticulate materials may be used for the supply or may contain antimicrobial materials. The nanoparticles and antibiotics based on metal and metal oxides are seen as promising therapeutic candidates for future applications of biomedical science, because they have lower toxicity and improved antibacterial, antiviral, and cancer efficacy. They are of unique size, such as an increased volume-to-surface ratio, making them efficient medicine carriers and improving their solubility, compatibility, and ease of delivery (31).

Advancing genetic engineering and next-generation sequence have enabled scientists to develop future strategies, such as bioengineered probiotics or pharmabiotics, that can become a bacterial infection biotherapy or prophylaxis. An option against antibiotics may be bioengineered probiotics with diverse immunogenic properties. Recombinant probiotics with high competence could provide a greater degree of site specificity than common drug administration regimes to produce drugs, therapeutic proteins, and gene therapy vectors (24).

Conclusion

The regular data collected by different organizations play a vital role in monitoring the status of AMR and antimicrobial usage by humans and livestock. These annual reports have highly helped the government to decide for alternatives and have focused in many training activities to combat the AMR situation globally. AMR prevention is linked to the One Health concept. As antibiotic resistance genes persist on an interface between environment and animal health, an approach is required in all three areas that stresses the concept of “One Approach to Health.” Finally, at any stage of life, antibiotic resistance can affect humans or animals. Alternative therapies should be developed to reduce dependency on chemical therapy. As antibiotics become part of modern medicine before many decades, antibiotic effectiveness is decreasing. Clinical research, microbiology, genetics and computer engineering, imaging and modeling experts should work together to develop strategies to deal with this problem and to develop new therapies. Patients with normal infections should avoid unnecessary prescription and over-prescription of antibiotics and patients should be advised to follow good hygiene such as hand washing and adequate infection management measures.

For the purpose of addressing the global epidemic of drug-resistant infections, an accurate evaluation of the existing and future burden of diseases caused by AMR is crucial. To effectively combat an apparent rise in resistance infections, detailed and dynamic information is required. This information enables policymakers and healthcare professionals to put global AMR action plans into place and allocate resources in an effective manner (32). The standard and accessibility of the supplied data affect how accurate AMR results will be. The current state of the global surveillance system is unconnected and unsatisfactory (33). Only 70 nations have reportedly signed up for the WHO’s Global Antimicrobial Resistance Surveillance System. The percentage is fewer than half of the AMR rates reported (34). Numerous restrictions, such as a lack of adequate global data, make it difficult to quantify AMR reports. Many countries lack the lab and data management capabilities needed to conduct efficient surveillance. Most significantly, surveillance data or analysis cannot remedy the problem right away; they can only estimate the burden that will arise. Only the creation of brand-new anti-pathogenic chemicals and herbal formulations can fix the problem. The exchange of data is also further constrained by many necessary and strict privacy concerns. More difficulties for the researchers are brought about by the lack of extensive and diverse datasets from various places, which is especially troubling in low-income countries where monitoring is essentially nonexistent.

Disclosures

Conflict of interest: The authors declare no conflict of interest.Financial support: This research was supported by two industry-academia collaboration projects. VtR Inc-CGU, R.O.C. project grant #SCRPD1L0221 and DOXABIO-CGU, R.O.C. project grant #SCRPD1K0131; it was additionally supported by CGU project grant #UZRPD1M0081.

Authors contribution: All authors contributed equally to this article.