Antibiotic use in people and pigs: a One Health survey of rural residents' knowledge, attitudes and practices in Shandong province, China.

Objectives: To evaluate rural residents' knowledge, attitudes and practices (KAP) towards antibiotic use in humans and pigs, among individuals with and without backyard pig farms living in Shandong province, China. Methods: We conducted a cross-sectional questionnaire study among residents in 12 villages, and directly observed medicines stored in households for humans and pigs. Results: In total, 769 residents participated, including 330 backyard pig farmers. Respondents had low levels of knowledge about antibiotics. A quarter of participants had bought one or more antibiotics from a pharmacy without a prescription in the previous year, and this was more common among pig farmers who had bought antibiotics for their pigs without consulting a vet (49% versus 25%, P < 0.001). Stored antibiotics for human use were found in 42% of households, and 70% of participants from these households did not know they were storing antibiotics. Thirty-one percent of backyard pig farmers were storing antibiotics for pig use. Farmers who thought it was good to store leftover antibiotics for their pigs were more likely to have stored antibiotics for pigs (41% versus 20%) and for humans (47% versus 32%; both P < 0.01). A fifth of participants thought their own actions were important for controlling antibiotic resistance. Conclusions: We found differences in the KAP of backyard pig farmers and non-pig farmers to antibiotics, and parallels between pig farmers' attitudes and behaviours towards antibiotic use in pigs and in humans. Our findings reinforce the need for context-adapted multifaceted interventions to improve antibiotic use and provide suggestions for targeting educational approaches.

Public health risk of antimicrobial resistance transfer from companion animals.

Antimicrobials are important tools for the therapy of infectious bacterial diseases in companion animals. Loss of efficacy of antimicrobial substances can seriously compromise animal health and welfare. A need for the development of new antimicrobials for the therapy of multiresistant infections, particularly those caused by Gram-negative bacteria, has been acknowledged in human medicine and a future corresponding need in veterinary medicine is expected. A unique aspect related to antimicrobial resistance and risk of resistance transfer in companion animals is their close contact with humans. This creates opportunities for interspecies transmission of resistant bacteria. Yet, the current knowledge of this field is limited and no risk assessment is performed when approving new veterinary antimicrobials. The objective of this review is to summarize the current knowledge on the use and indications for antimicrobials in companion animals, drug-resistant bacteria of concern among companion animals, risk factors for colonization of companion animals with resistant bacteria and transmission of antimicrobial resistance (bacteria and/or resistance determinants) between animals and humans. The major antimicrobial resistance microbiological hazards originating from companion animals that directly or indirectly may cause adverse health effects in humans are MRSA, methicillin-resistant Staphylococcus pseudintermedius, VRE, ESBL- or carbapenemase-producing Enterobacteriaceae and Gram-negative bacteria. In the face of the previously recognized microbiological hazards, a risk assessment tool could be applied in applications for marketing authorization for medicinal products for companion animals. This would allow the approval of new veterinary medicinal antimicrobials for which risk levels are estimated as acceptable for public health.

Variations in the sales and sales patterns of veterinary antimicrobial agents in 25 European countries.

OBJECTIVES: To describe sales and sales patterns of veterinary antimicrobial agents in 25 European Union (EU)/European Economic Area (EEA) countries for 2011. METHODS: Data on the sales of veterinary antimicrobial agents from 25 EU member states and EEA countries for 2011 were collected at package level (name, formulation, strength, pack size, number of packages sold) according to a standardized protocol and template and presented in a harmonized manner. These data were calculated to express amounts sold, in metric tonnes, of active ingredient of each package. A population correction unit (PCU) was applied as a proxy for the animal biomass potentially treated with antimicrobial agents. The indicator used to express sales was milligrams of active substance per PCU. RESULTS: Substantial variations in the sales patterns and in the magnitude of sales of veterinary antimicrobial agents, expressed as mg/PCU, between the countries were observed. The proportion of sales, in mg/PCU, of products applicable for treatment of groups or herds of animals (premixes, oral powders and oral solution) varied considerably between the countries. CONCLUSIONS: Some countries reported much lower sales of veterinary antimicrobial agents than others, when expressed as mg/PCU. Sales patterns varied between countries, particularly with respect to pharmaceutical forms. Further studies are needed to understand the factors that explain the observed differences.

Pleuromutilins: use in food-producing animals in the European Union, development of resistance and impact on human and animal health.

Pleuromutilins (tiamulin and valnemulin) are antimicrobial agents that are used mainly in veterinary medicine, especially for swine and to a lesser extent for poultry and rabbits. In pigs, tiamulin and valnemulin are used to treat swine dysentery, spirochaete-associated diarrhoea, porcine proliferative enteropathy, enzootic pneumonia and other infections where Mycoplasma is involved. There are concerns about the reported increases in the MICs of tiamulin and valnemulin for porcine Brachyspira hyodysenteriae isolates from different European countries, as only a limited number of antimicrobials are available for the treatment of swine dysentery where resistance to these antimicrobials is already common and widespread. The loss of pleuromutilins as effective tools to treat swine dysentery because of further increases in resistance or as a consequence of restrictions would present a considerable threat to pig health, welfare and productivity. In humans, only one product containing pleuromutilins (retapamulin) is authorized currently for topical use; however, products for oral and intravenous administration to humans with serious multidrug-resistant skin infections and respiratory infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA), are being developed. The objective of this review is to summarize the current knowledge on the usage of pleuromutilins, resistance development and the potential impact of this resistance on animal and human health.

Outbreaks of methicillin-resistant Staphylococcus aureus among staff and dogs in Swedish small animal hospitals.

Methicillin-resistant Staphylococcus aureus (MRSA) was found in a dog for the first time in Sweden in 2006. Between October 2006 and May 2007, MRSA was diagnosed in 7 more dogs that had been treated in 3 different small animal hospitals, located 150-200 km apart, in different counties of Sweden. Screening of the animal hospital staff and environment in these small animal hospitals showed 20 of 152 staff to be positive for MRSA, with rates between 2% and 18% in the different hospitals, while all 128 environmental samples were negative. All MRSA isolates from dogs and staff belonged to spa type t032, were Panton-Valentine leukocidin (PVL)-negative, and had indistinguishable pulsed-field gel electrophoresis patterns, except for 2 isolates with closely related patterns. To our knowledge, this is the first report of multiple outbreaks of MRSA in dogs caused by the same strain within a short time frame, and appearing in a country with low prevalence of MRSA in both humans and dogs. This highlights the importance of infection control programs in animal hospitals and in animal health care. Awareness of MRSA as an occupational risk for veterinary personnel is essential.

Sales of veterinary antibacterial agents in nine European countries during 2005-09: trends and patterns.

OBJECTIVES: To identify trends and patterns of sales of veterinary antimicrobial agents in nine European countries during 2005-09 in order to document the situation. METHODS: Existing sales data, in tonnes of active ingredients, of veterinary antimicrobial agents by class were collected from nine European countries in a standardized manner for the years 2005-09 (one country for 2006-09). A population correction unit (PCU) is introduced as a proxy for the animal population potentially treated with antimicrobial agents. The sales data are expressed as mg of active substance/PCU. RESULTS: Data coverage was reported to be 98%-100% for the nine countries. Overall, sales of veterinary antimicrobials agents, in mg/PCU, declined during the reporting period in the nine countries. Substantial differences in the sales patterns and in the magnitude of sales of veterinary antimicrobial agents, expressed as mg/PCU, between the nine countries are observed. The major classes sold were penicillins, sulphonamides and tetracyclines. The sales accounted for by the various veterinary antimicrobial agents have changed substantially for most countries. An increase in the sales of third- and fourth-generation cephalosporins and fluoroquinolones were observed for the majority of the countries. CONCLUSIONS: Through re-analysis of existing data by application of a harmonized approach, an overall picture of the trends in the sales of veterinary antimicrobial agents in the nine countries was obtained. Notable differences in trends in sales between the countries were observed. Further studies, preferably including data by animal species, are needed to understand the factors that explain these observations.

Review on methicillin-resistant Staphylococcus pseudintermedius.

Staphylococcus pseudintermedius is an important opportunistic pathogen of companion animals, especially dogs. Since 2006 there has been a significant emergence of methicillin-resistant S. pseudintermedius (MRSP) mainly due to clonal spread. This article reviews research on MRSP with a focus on occurrence, methods used for identification, risk factors for colonization and infection, zoonotic potential and control options. Potential areas for future research are also discussed.

Clonal spread of methicillin-resistant Staphylococcus pseudintermedius in Europe and North America: an international multicentre study.

OBJECTIVES: The aim of this study was to determine the phenotypic and genotypic resistance profiles of methicillin-resistant Staphylococcus pseudintermedius (MRSP) and to examine the clonal distribution in Europe and North America. METHODS: A total of 103 MRSP isolates from dogs isolated from several countries in Europe, the USA and Canada were characterized. Isolates were identified by PCR-restriction fragment length polymorphism (RFLP), antimicrobial susceptibility was determined by broth dilution or gradient diffusion, and antimicrobial resistance genes were detected using a microarray. Genetic diversity was assessed by multilocus sequence typing (MLST), PFGE and spa typing. Staphylococcal cassette chromosome mec (SCCmec) elements were characterized by multiplex PCR. RESULTS: Thirteen different sequence types (STs), 18 PFGE types and 8 spa types were detected. The hybrid SCCmec element II-III described in a MRSP isolate was present in 75 (72.8%) isolates. The remaining isolates either had SCCmec type III (n=2), IV (n=6), V (n=14) or VII-241 (n=4) or were non-typeable (n=2). The most common genotypes were ST71(MLST)-J(PFGE)-t02(spa)-II-III(SCCmec) (56.3%) and ST68-C-t06-V (12.6%). In addition to mecA-mediated beta-lactam resistance, isolates showed resistance to trimethoprim [dfr(G)] (90.3%), gentamicin/kanamycin [aac(6')-Ie-aph(2')-Ia] (88.3%), kanamycin [aph(3')-III] (90.3%), streptomycin [ant(6')-Ia] (90.3%), streptothricin (sat4) (90.3%), macrolides and/or lincosamides [erm(B), lnu(A)] (89.3%), fluoroquinolones (87.4%), tetracycline [tet(M) and/or tet(K)] (69.9%), chloramphenicol (cat(pC221)) (57.3%) and rifampicin (1.9%). CONCLUSIONS: Two major clonal MRSP lineages have disseminated in Europe (ST71-J-t02-II-III) and North America (ST68-C-t06-V). Regardless of their geographical or clonal origin, the isolates displayed resistance to the major classes of antibiotics used in veterinary medicine and thus infections caused by MRSP isolates represent a serious therapeutic challenge.

Decreased detection of ESBL- or pAmpC-producing Escherichia coli in broiler breeders imported into Sweden.

In the spring of 2010, it was discovered that a large proportion of broilers in Sweden were colonized with Escherichia coli producing extended-spectrum beta-lactamases (ESBL) or plasmid mediated AmpC (pAmpC). It was hypothesized that the high prevalence was due to transfer from an upper level in the production pyramid and sampling upwards in the production pyramid was initiated. From 2010 to 2019, all shipments (n = 122) of broiler breeders were screened on arrival to Sweden for the occurrence of ESBL- or pAmpC-producing E. coli using selective methods. Samples of paper linings from shipments of breeders were cultured on MacConkey agar supplemented with cefotaxime (1 mg/L) after pre-enrichment in either MacConkey broth with cefotaxime (1 mg/L), or from late June 2015 in buffered peptone water without antibiotics. ESBL- or pAmpC-producing E. coli was isolated from 43 (35%) of these. Over the years, the proportion of positive imports have decreased and during 2018 and 2019 all imports were negative. In conclusion, the occurrence of ESBL- or pAmpC-producing E. coli in broiler breeders on arrival to Sweden has decreased. Such bacteria have not been detected in any shipments since 2017.

A link between the newly described colistin resistance gene mcr-9 and clinical Enterobacteriaceae isolates carrying blaSHV-12 from horses in Sweden.

OBJECTIVES: The aim of this study was to investigate the occurrence of the newly described transferable colistin resistance gene mcr-9 in extended-spectrum ß-lactamase (ESBL)-producing clinical Enterobacteriaceae isolates from horses in Sweden. METHODS: A total of 56 whole-genome sequenced ESBL-producing Enterobacteriaceae isolates from horses were subjected to in silico detection of antimicrobial resistance genes and identification of plasmid replicons types. The colistin minimum inhibitory concentration (MIC) for mcr-positive isolates was determined by broth microdilution. Relatedness between Enterobacteriaceae carrying mcr genes was determined by multilocus sequence typing (MLST) and core genome MLST. RESULTS: Thirty ESBL-producing Enterobacteriaceae isolates from horses were positive for the colistin resistance gene mcr-9. These isolates included Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca and Citrobacter freundii and belonged to diverse MLST sequence types within each species. Two of the mcr-9-containing isolates originated from the same horse. All mcr-9-positive isolates had colistin MICs below or equal to the EUCAST epidemiological cut-off value of 2 mg/L and were negative for the two potential regulatory genes qseB-like and qseC-like for mcr-9. Except for one isolate carrying only blaTEM-1B, all of the isolates carried blaSHV-12 and blaTEM-1B, and were all considered multidrug-resistant as they harboured genes encoding resistance to aminoglycosides, chloramphenicol, fosfomycin, macrolides, quinolones, sulfonamides, trimethoprim and tetracyclines. Plasmid replicon types IncHI2 and IncHI2A were detected in all mcr-9-positive isolates. CONCLUSION: The occurrence of mcr-9 was common among clinical ESBL-producing Enterobacteriaceae isolates from horses in Sweden and was linked to the ESBL-encoding gene blaSHV-12 and plasmid replicon types IncHI2 and IncHI2A.

Knowledge, attitudes and practices relating to antibiotic use and antibiotic resistance among backyard pig farmers in rural Shandong province, China.

China is among the world's largest consumers of antibiotics for livestock, and the demand for meat protein continues to rise. Pig production takes place at a range of facilities, including backyard pig farms. The aim of this study was to describe the knowledge, attitudes and practices of backyard pig farmers concerning antibiotic use and resistance, and to observe household storage of antibiotics for use in pigs. We conducted a cross-sectional questionnaire survey among 271 rural residents with backyard pig farms in 12 villages in one town in Shandong province. The median number of pigs per backyard farm was 14, and 82 % (222/271) of participants reported not having had any training about raising pigs. Eighteen percent of participants (48/271) reported always or often adding antibiotics to feed to keep pigs healthy and prevent diseases, and a third (88/271) of participants believed that pigs should be given antibiotics when they stop eating. Thirty percent (82/271) reported having bought antibiotics in the previous year without having first spoken with a veterinarian. Antibiotics accounted for over half of all medicines stored (55 %, 197/358), and were observed in 31 % of all households (83/271). Less than half of participants (45 %, 37/83) from households in which antibiotics for pig use were found knew that they were storing antibiotics. The most common class of antibiotics stored for use in pigs was (Q)J01C beta-lactam antibiotics, penicillins (19 %, 37/197), followed by (Q)J01F macrolides, lincosamides and streptogramins (14 %, 28/197), and (Q)J01M quinolones (12 %, 25/197). These results provide important insights into how backyard pig farmers are using antibiotics in rural China and suggest potential targets for interventions to reduce unnecessary and inappropriate use.

The rise and fall of a vancomycin-resistant clone of Enterococcus faecium among broilers in Sweden.

OBJECTIVES: Historically, vancomycin-resistant enterococci (VRE) have been very common among farm animals in Europe, and they can still be readily isolated using media supplemented with vancomycin. An increase in the occurrence of VRE among broilers in Sweden was reported during 2000-2005. This was due to the spread of one clone of VRE in the apparent absence of selective pressure. The aims of this study were to estimate the current occurrence of VRE among Swedish broilers and to investigate if there had been any changes with regards to the dominating clone and antimicrobial resistance pattern. METHODS: Caecal samples (n=100) collected at slaughter from healthy broilers were cultured on Slanetz-Bartley agar supplemented with vancomycin (16 mg/L). Presumptive VRE were identified to species using MALDI-TOF MS, susceptibility tested using broth micro-dilution, and whole genome sequenced to investigate the genetic relationship with previous isolates. RESULTS: Eleven (11%) of the samples were positive for VRE. This was a statistically significant decrease in the proportion of positive samples from 2010. The same clone as before still prevailed. CONCLUSIONS: The occurrence of VRE among broilers in Sweden has decreased. However, just as the occurrence of VRE among Swedish broilers increased in the apparent absence of selective pressure, the reasons for the decrease is unknown.

The potential role of concentrated animal feeding operations in infectious disease epidemics and antibiotic resistance.

The industrialization of livestock production and the widespread use of nontherapeutic antimicrobial growth promotants has intensified the risk for the emergence of new, more virulent, or more resistant microorganisms. These have reduced the effectiveness of several classes of antibiotics for treating infections in humans and livestock. Recent outbreaks of virulent strains of influenza have arisen from swine and poultry raised in close proximity. This working group, which was part of the Conference on Environmental Health Impacts of Concentrated Animal Feeding Operations: Anticipating Hazards--Searching for Solutions, considered the state of the science around these issues and concurred with the World Health Organization call for a phasing-out of the use of antimicrobial growth promotants for livestock and fish production. We also agree that all therapeutic antimicrobial agents should be available only by prescription for human and veterinary use. Concern about the risk of an influenza pandemic leads us to recommend that regulations be promulgated to restrict the co-location of swine and poultry concentrated animal feeding operations (CAFOs) on the same site and to set appropriate separation distances.

Building bridges to operationalise one health - A Sino-Swedish collaboration to tackle antibiotic resistance.

Antibiotic resistance is a complex global health challenge. The recent Global Action Plan on antimicrobial resistance highlights the importance of adopting One Health approaches that can cross traditional disciplinary boundaries. We report on the early experiences of a multisectoral Sino-Swedish research project that aims to address gaps in our current knowledge and seeks to improve the situation through system-wide interventions. Our research project is investigating antibiotic use and resistance in a rural area of China through a combination of epidemiological, health systems and laboratory investigations. We reflect here on the challenges inherent in conducting long distance cross-disciplinary collaborations, having now completed data and sample collection for a baseline situation analysis. In particular, we recognise the importance of investing in aspects such as effective communication, shared conceptual frameworks and leadership. We suggest that our experiences will be instructive to others planning to develop similar international One Health collaborations.

Antimicrobial usage in 60 Swedish farrow-to-finish pig herds.

The aim of this study was to quantify antimicrobial consumption in Swedish farrow-to-finish pig herds. Sixty herds with 100 sows or more producing more than 500 fatteners per year participated in a study where data on antimicrobial consumption over a period of one year were collected. Data on antimicrobial use were collected by substance, administration route and per age category. Antimicrobial use was measured as defined daily doses and expressed as treatment incidence (TI) per 1000 pig-days at risk. The TIs for growing pigs varied between herds, from 1.6 to 116.0 with a median of 14.3. The highest TI was recorded for suckling piglets with a median of 54.7 (range; 1.6-367.9), while the median TIs for weaners, fatteners and adults were 6.2, 2.8 and 8.4, respectively (range; 0.0-260.5; 0.0-64.9; 0.0-45.0, respectively). The within herd TIs for the different age categories were not correlated. Individual treatment, mainly consisting of injectables, was the most common form of application except for weaners for which a majority (54.8%) of the treatments were group treatments. Benzylpenicillin was the most commonly applied substance except for weaners for which oral formulations of tylosin were most common. For fatteners, group treatments constituted 8.4% of the total TI. Group treatments with oral colistin were applied to suckling piglets in five herds. Group treatments were not applied to adult pigs. The TI for weaners was significantly lower for specific pathogen-free herds. The results show that the overall antimicrobial use in Swedish farrow-to-finish pig herds varied to a great extent, and the between-herd variation indicates that there is room for improvement of pig health. Targeting suckling piglets may be most beneficial, but further studies are required to identify specific focus areas which may reduce the need for antimicrobials in this particular age group.

A tissue cage model in calves for studies on pharmacokinetic/pharmacodynamic interactions of antimicrobials.

An in vivo model for studies of pharmacokinetic/pharmacodynamic (PK/PD) interactions of antimicrobials was developed. Tissue cages with a constant surface area but with different volumes were implanted in calves and infected with Mannheimia haemolytica. Penicillin was injected directly into the cages. With this procedure, different concentration-time profiles could be simulated so that the effect of a range of PK/PD indices on the infection could be monitored. The area under the curve to minimum inhibitory concentration (MIC) and time above MIC were equally predictive for effect, but Cmax to MIC was not. If drug dosages in relation to the MIC of strains used for infection are optimised, the model offers an interesting alternative to explore relevant factors for drug dosage optimisation.

Exudative epidermitis and porcine circovirus-2 infection in a Swedish SPF-herd.

An outbreak of exudative epidermitis (EE) among piglets in a Swedish SPF-herd initiated a survey for indications as to the cause of disease. The herd was established by caesarean section and has been closed to all new animal material, with the exception of semen for artificial insemination (AI). The study comprised serum samples from the SPF-herd over a 10-year period (n=109) and a close monitoring of animals in the herd during the period after the EE outbreak. Serum samples from conventional boars at the AI-station servicing the herd were also included (n=9). All serum samples were tested for antibodies to porcine circovirus-2 (PCV-2). In addition, 3-week-old piglets from three litters (n=24) farrowed close after the initial EE outbreak were closely monitored for clinical signs of skin disease, sampled for Staphylococcus hyicus, tested for antibodies to porcine parvovirus and in sequentially collected serum samples tested for interferon-alpha (IFN-alpha) and interleukin-6. The PVC-2 serology showed that animals in the herd were sero-negative at least until 2 months prior to the EE outbreak. During the period close after the EE outbreak the animals showed varying levels of antibodies to PCV-2 but all the tested animals had sero-converted 4 months later. The AI boars were also sero-positive to PCV-2 at the time of the EE outbreak. Animals in the SPF-herd remained sero-positive to PCV-2 during the following 7 years. In the monitored litters, one piglet had clinical EE and 15 piglets displayed defined erythemas on the abdomen. Fourteen of the piglets also had IFN-alpha in serum on one or more occasions during the study, indicating viral activity among the animals. S. hyicus was isolated from all of the piglets from the earliest sampling point (3 days of age) and onwards, irrespective of clinical signs. PCV-2 was isolated from lymph node tissue collected from one of the EE affected pigs.Further, increases in the number of stillborn piglets, small litters (<6 piglets) and repeat breeders could be correlated to the time of PCV-2 sero-conversion. Coincidence of active viral infection and sero-conversion to PCV-2 points to the virus as the cause of the EE outbreak and reproductive disturbances.