Antibiotic Resistance Spread and Resistance Control Options. Estonian Experience

Abstract Antibiotic resistance refers to the ability of microbes to grow in the presence of an antibiotic that would have originally killed or inhibited the growth of these microorganisms. Microorganisms resistant to antibiotics exist in humans, animals and in the environment. Resistant microbes can spread from animals to humans and vice versa either through direct contact or through the environment. Resistant bacteria survive in the body during a course of antibiotics and continue to multiply. Treatment of antibiotic-resistant infections takes more time, costs more, and sometimes may prove impossible. The aim of the AMR-RITA project was to develop recommendations based on scientific evidence including the “One Health” principle for the formulation of policy on antibiotic resistance. In order to achieve the goal, the role of human behaviour, human and animal medicine, and the environment was implicated in the development of antibiotic resistance. The evaluation of the resistance spread routes, risks and levels, and the possible measures to control the spread of antibiotic resistance were identified. Topics related to antibiotic resistance were analysed in medicine, veterinary medicine and environment subsections. Existing data were combined with new data to assess the transmission routes and mechanisms of antibiotic resistance. For this purpose, samples were collected from people, animals, food, and the environment. The analysis of the samples focused on the main resistent organisms, resistance genes and antibiotic residues. As a result of the study, we conclude that the use of antibiotics in Estonia is generally low compared to other European countries. However, there are bottlenecks that concern both human and veterinary medicine. In both cases, we admit that for some diagnoses there were no treatment guidelines and antibiotics were used for the wrong indications. The lack of specialists of clinical microbiology is a problem in Estonain hospitals. For example, many hospitals lack an infection control specialist. The major worrying trends are the unwarranted use of broad-spectrum antibiotics in humans and the high use of antibiotics critical for human medicine (cephalosporins, quinolones) in the teratment of animals. If more antibiotics are being used, resistance will also spread. We found that those cattle farms that use more cephalosporins also have higher levels of resistance (ESBL-mediated resistance). It also turned out that genetically close clusters of bacteria are often shared by humans and animals. This is evidence of a transfer of resistance between species. However, such transfer occurs slowly, and we did not detect any transfer events in the recent years. Antibiotic residues, just like other drug residues, can reach the environment. The use of slurry and composted sewage sludge as fertilizer are the main pathways. We detected fluroquinolones and tetracyclines in comparable concentrations in slurry and uncomposted sewage sludge. Composting reduces the content of drug residues, and the efficiency of the process depends on the technology used. In addition to antibiotic residues, we also determined some other drug residues accumulating in the environment. High levels of diclofenac and carbamazepine in surface water are a special concern. These are medicines for human use only, so they reach the environment through sewage treatment plants. Based on the results obtained during the research, we propose a series of evidence-based recommendations to the state for the formulation of antimicrobial resistance policy. We propose that Estonia needs sustainable AMR surveillance institution, which (1) continuously collects and analyses data on the use of antimicrobials and antimicrobial resistance and provides regular feedback to relevant institutions (state, health and research institutions), (2) assesses the reliability of the data and ensures carrying out additional and confirming studies, (3) coordinates the activities of national and international research and monitoring networks and projects. We recommend creation of a competence centre that would deal with the topic of AMR across all fields. This should also include funding for research. Competing Interest Statement The authors have declared no competing interest. Funding Statement The study was commissioned and funded by the Estonian Research Agency with support from the European Regional Development Fund of the program "Strengthening of sectoral research and development" (RITA) activity 1 "Strategic TA supporting activity". The study was completed in the period July 1, 2019 - June 31, 2022 to implement the objectives of the Ministry of Rural Affairs, the Ministry of Social Affairs the Ministry of the Environment. The research budget was 947,370 euros. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Tartu Ethics Committee I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors Abbreviations - AMR - antibiotic resistance (antimicrobial resistance) - ATC classification - anatomical-therapeutic-chemical classification - DDD - defined daily dose - ECDC - European Center for Disease Prevention and Control control - ESAC-Net - European surveillance network of consumption of antimicrobial substances (European Surveillance of Antimicrobial Consumption Network) - ESBL - extended-spectrum beta-lactamase - EUCAST - European Committee for Antimicrobial Susceptibility Testing - MIC - minimum inhibitory concentration - MRSA - methicillin-resistant Staphylococcus aureus - PCU - population correction unit - PAP - purchased antibiotic prescription - ST - sequence type - BD - bed day - VRE - vancomycin-resistant enterococcus