Monitoring of antibiotic resistance
‘Antibiotic’ means a substance produced by living microbes that kills or inhibits the growth of other microbes (in the present context, this also includes compounds that are partly or fully synthetically produced). Antibiotics have been used since the 1930s to treat infectious diseases in humans and animals. The word ’antibiotic’ also covers antifungal, antiparasitic and antiviral preparations, but only antibiotics with antibacterial effects are discussed here.
Modes of action of antibiotics
Some antibiotics are capable of killing the target bacteria, while some only inhibit their growth. In the latter case in particular, the bacteria are ultimately killed by the body’s own defence mechanisms. Antibiotics may, among other things, affect bacterial cell wall structures, protein synthesis or nucleic acid metabolism. Antibiotics have action spectra of varied width. Some are effective against many bacterial species (‘broad-spectrum antibiotics’) while others have effect only against certain species (‘narrow-spectrum antibiotics’).
The natural resistance of bacteria is a characteristic typical of a certain bacterial genus or species. Acquired resistance refers to a phenomenon whereby strains originally susceptible to a specific antibiotic substance become resistant to it, due to, for example, a genetic mutation. There are various kinds of resistance mechanisms. Bacteria may produce enzymes that break down antibiotics, or the antibiotic’s binding site or site of action in the target structure may change. Some bacteria are capable of hindering the entrance of an antibiotic through their cell wall or effectively pumping it out of the bacterial cell. Certain resistance mechanisms are based on alternative metabolic pathways. Multiresistant bacteria exhibit simultaneous resistance to several antibiotic groups. Over the past few years, the prevalence of antibiotic resistant bacteria has rapidly increased and resistance mechanisms have become more varied. Increasing antibiotic resistance also increases human and animal morbidity and mortality and heath care costs, which is why antibiotic resistance has become one of the most severe threats to human and veterinary medicine.
FINRES-Vet resistance monitoring programme
In Finland, a programme for monitoring antibiotic resistance, FINRES-Vet, has been underway since 2002. The programme monitors the antibiotic susceptibility of zoonotic bacteria (pathogenic bacteria that can spread between animals and humans), certain animal pathogens, and indicator bacteria. In addition to the resistance situation, the programme also monitors the use of feed additives and the consumption of veterinary antibiotics. In addition to Evira, the Finnish Medicines Agency Fimea is also involved in the implementation of the FINRES-Vet programme. From 2012 onwards, resistance data from pet animals have been gathered in the clinical microbiology laboratory of the Department of Equine and Small Animal Medicine in the Faculty of Veterinary Medicine, University of Helsinki. At present, resistance monitoring in EU countries is based on the EU legislation (Decision 2013/652/EU), which specifies the bacterial and animal species and food stuffs to be included. FINRES-Vet program is carried out based on the EU legislation as well as national decisions.
The indicator bacteria included in the programme are present in the normal intestinal bacterial flora of healthy animals. Resistance occurring in these bacteria is regarded to reflect the spectrum and frequency of the antibiotic treatments used in the animal populations concerned. Indicator bacteria are also considered of being capable of functioning as a pool of resistance factors from which these factors can transmit to animal or human pathogens. Indicator bacteria are isolated from bovines, pigs and broilers and the animal species is changed on an annual basis. In the FINRES-Vet programme, the broth microdilution method is mainly used for susceptibility testing, and the bacteria are classified as susceptible or resistant based on their epidemiological cut-off values. Bacterial populations can be divided into susceptible or ‘wild type’ and resistant or ‘non-wild type’ populations. Significant changes and trends in the occurrence of resistance can be observed by applying the epidemiological cut-off values to the analysis of the populations conducted at regular intervals. The programme also provides information about the occurrence of novel resistance mechanisms in Finland, and the correlation between the occurrence of resistance and the consumption of antimicrobials. Acquired information can be utilized when varied measures are taken to prevent the spread of antibiotic resistance, when recommendations for the use of antibiotics are given, and as the impacts of these recommendations are assessed. The information obtained from the programme can also be used for assessing the risks associated with human and animal health.
Results of the FINRES-Vet programme have been collected into summaries published at regular intervals. The latest summary, comprising years 2010 to 2012, is available online in its entirety at the Evira website. Expressed as kilograms of active substance, a total of 13,700 kg of veterinary antibiotics were sold in Finland during 2014. The sales of veterinary antibiotics have been stable in the 2010s with an annual average of 13 500 kg of active substance. As the data on consumption volumes are based on product-specific statistics provided by pharmaceutical wholesalers, they cannot be used for reliably calculating the amounts of antibiotics administered to different animal species. The product most widely used for animals is injectable penicillin. The use of antibiotic feed additives are no longer allowed for animal growth promotion in the EU countries. More information on the sales of veterinary medicines in Finland can be found at the Fimea website.
Of the zoonotic bacteria, salmonella is only rarely found in the Finnish food-producing animals or foods of animal origin, for which reason the number of strains subjected to susceptibility testing is also small. The tested strains have in most cases been highly susceptible to antibiotics. The proportion of resistant Campylobacter isolates is also low on international comparison. Noteworthy, though, is the increase of fluoroquinolone resistant isolates from the studied food-producing animal species in years 2010-2014. A quarter of all studied C. jejuni isolates from broilers were resistant to ciprofloxacin in 2014. In previous years, ciprofloxacin resistance has been rare in broiler campylobacters and in 2015, no strains resistant to ciprofloxacin were found. Ciprofloxacin resistance became more prevalent also in bovine and swine campylobacters in 2010-2013, when bacteria isolated from these species were previously studied.
Resistance was rare or unusual in indicator bacteria isolates from bovines and broilers. However, broilers in particular are only treated with antibiotics during the growth period in highly exceptional circumstances. In indicator E. coli from pigs, resistance was most commonly detected against ampicillin, tetracycline, sulfamethoxazole and trimethoprim. The resistance situation of certain animal pathogenic bacteria is disconcerting. For example, E. coli isolated from pig enteritis is commonly multiresistant. Also, canine Staphylococcuspseudintermedius bacteria have been resistant to several antibiotics for more than a decade. In 2012, already 16% of cat and dog S. pseudintermedius-strains were resistant to methicillin (so called MRSP bacteria). Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria have also been occasionally found in companion animals and horses. In 2012, 4.3% of E. coli bacteria isolated from cats and dogs were ESBL-producers.
The occurrence of ESBL-producers is also monitored from food-producing animals according to the EU monitoring program, every other year from poultry and bovines/pigs. In Finland, ESBL-producers have been only rarely found in pigs, bovines or their meat but the situation is worse in imported poultry flocks. For example, in 2015, 20% of the studied imported broiler flocks were found to have ESBL-producers while seven percent of the domestically slaughtered broiler flocks were ESBL-positive in 2014. Methicillin resistant Staphylococcus aureus (MRSA) strains have occasionally been found in horses, dogs and cats. The samples obtained from pig farms and received by Evira for examination during 2009–2010 yielded an apparent prevalence of around 15% of the pig farms. A new one-year survey of the prevalence of MRSA in slaughter pigs has been started in Evira in September 2016.