The use of aminoglycosides in animals within the EU: development of resistance in animals and possible impact on human and animal health: a review.

Aminoglycosides (AGs) are important antibacterial agents for the treatment of various infections in humans and animals. Following extensive use of AGs in humans, food-producing animals and companion animals, acquired resistance among human and animal pathogens and commensal bacteria has emerged. Acquired resistance occurs through several mechanisms, but enzymatic inactivation of AGs is the most common one. Resistance genes are often located on mobile genetic elements, facilitating their spread between different bacterial species and between animals and humans. AG resistance has been found in many different bacterial species, including those with zoonotic potential such as Salmonella spp., Campylobacter spp. and livestock-associated MRSA. The highest risk is anticipated from transfer of resistant enterococci or coliforms (Escherichia coli) since infections with these pathogens in humans would potentially be treated with AGs. There is evidence that the use of AGs in human and veterinary medicine is associated with the increased prevalence of resistance. The same resistance genes have been found in isolates from humans and animals. Evaluation of risk factors indicates that the probability of transmission of AG resistance from animals to humans through transfer of zoonotic or commensal foodborne bacteria and/or their mobile genetic elements can be regarded as high, although there are no quantitative data on the actual contribution of animals to AG resistance in human pathogens. Responsible use of AGs is of great importance in order to safeguard their clinical efficacy for human and veterinary medicine.

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.

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.

Environmental and public health related risk of veterinary zinc in pig production - Using Denmark as an example.

At great economic cost, important steps have been taken over the last many decades to reduce and control emissions of heavy metals in order to protect the environment and public health. Monitoring has confirmed the success of these policies with progressive declines of heavy metals in for example air, sewage sludge and environmental samples. For zinc, such improvements may nevertheless be counter-acted by its widely usage as a feed additive and veterinary medicinal product to piglets in the post-weaning period resulting in reduced occurrence of diarrhea and improvement of daily weight gain. This review therefore focuses on two major concerns associated with veterinary use of zinc, namely the quantifiable risks to the environment and promotion of (multi) resistant bacteria like LA-MRSA in pig farms. Denmark is used as an informed and realistic worst-case scenario, representing the largest pig production per capita in Europe. It is furthermore, one of the countries where most recent information can be found regarding soil monitoring data and zinc consumption within the pig production. An average increase in soil concentration by >45% was recently reported within the period 1998-2014. In order to predict future risk, this review presents new and simplified model predictions using current soil concentrations, annual load rates and predicted accumulation rates. In conclusion, it is estimated that within 25 years, continued agricultural practice of current zinc loads may result in a situation where almost all soils receiving manure from intensive piglet production may be at risk, but also other pig production types may result in scenarios with predicted risk to soil dwelling species, especially in sandy soils. Besides the quantifiable risks to soil ecosystems, high levels of zinc furthermore co-select for the persistence of LA-MRSA CC398 and other resistant bacteria on pig farms.

Do antimicrobial mass medications work? A systematic review and meta-analysis of randomised clinical trials investigating antimicrobial prophylaxis or metaphylaxis against naturally occurring bovine respiratory disease.

A distinct difference between veterinary and human medicine is the routine use of antimicrobial mass medications (prophylaxis, metaphylaxis) to healthy individuals. The need for antimicrobial mass medications is based on beliefs that group/s of animals will contract a bacterial disease (i.e. morbidity) and/or die (i.e. mortality). Bovine respiratory disease (BRD) represents the major indication for cattle antimicrobials worldwide. The objectives were to perform a systematic review and meta-analysis of randomised controlled clinical trials (RCTs) for naturally occurring BRD investigating antimicrobial prophylaxis/metaphylaxis to prevent morbidity/mortality. In total, 58 publications met the inclusion criteria summarizing 169 individual RCTs, spanning 50 years (1966-2016). Antimicrobial prophylaxis and metaphylaxis demonstrated moderate, yet highly variable relative risk reductions in BRD morbidity. These were dependent on the antimicrobial classes used, dependent on metaphylaxis definition, BRD attack rates and duration of the RCTs. Best relative risk reductions were from broad-spectrum critically important antimicrobials, or combinations. BRD prophylaxis/metaphylaxis represents major antimicrobial consumption for highly variable short-term gains in absolute risk reduction of morbidity/mortality. Despite widespread use of prevention products, the need for antimicrobial mass medications should be re-evaluated since the underlying problem is more likely the segmented infrastructure of the feedlot and veal calf industries compared to the disease itself.

Macrolides and lincosamides in cattle and pigs: use and development of antimicrobial resistance.

Macrolides and lincosamides are important antibacterials for the treatment of many common infections in cattle and pigs. Products for in-feed medication with these compounds in combination with other antimicrobials are commonly used in Europe. Most recently approved injectable macrolides have very long elimination half-lives in both pigs and cattle, which allows once-only dosing regimens. Both in-feed medication and use of long-acting injections result in low concentrations of the active substance for prolonged periods, which causes concerns related to development of antimicrobial resistance. Acquired resistance to macrolides and lincosamides among food animal pathogens, including some zoonotic bacteria, has now emerged. A comparison of studies on the prevalence of resistance is difficult, since for many micro-organisms no agreed standards for susceptibility testing are available. With animal pathogens, the most dramatic increase in resistance has been seen in the genus Brachyspira. Resistance towards macrolides and lincosamides has also been detected in staphylococci isolated from pigs and streptococci from cattle. This article reviews the use of macrolides and lincosamides in cattle and pigs, as well as the development of resistance in target and some zoonotic pathogens. The focus of the review is on European conditions.

Pharmacokinetics in pulmonary epithelial lining fluid and plasma of ampicillin and pivampicillin administered to horses.

Ampicillin concentrations in pulmonary epithelial lining fluid (PELF) and plasma was studied after single intravenous ampicillin administration (15mg/kg) or single intragastric administration of its prodrug, pivampicillin (19.9mg/kg) to horses and discussed in relation to minimum inhibitory concentrations (MIC) of common equine respiratory pathogens. After intravenous administration, elimination of ampicillin was fast and not detectable in plasma after 12h in three out of six horses. Pivampicillin was absorbed well in non-fasted horses with an oral bioavailability of 36%. The degree of penetration of ampicillin into PELF, as described by the AUC(PELF)/AUC(plasma) ratio from 0 to 12h was 0.40 after intravenous administration and 1.00 after pivampicillin administration. In horses, ampicillin administered either intravenously or orally, in the form of pivampicillin, can provide clinically relevant drug concentrations in PELF for at least 12h, when treating susceptible equine respiratory pathogens (e.g. streptococci). Treatment of other bacterial pathogens requires susceptibility testing and possibly more frequent dosing, depending of minimum inhibitory concentrations (MIC) values.