But the bacteria this drug was intended to fight have developed resistance over the past 60 years, and antibiotics have been losing their power. In both human and veterinary medicine there are now bacteria with a large number of antimicrobial resistances.

Researchers from the Department of Veterinary Medicine at Freie Universität are currently working to develop methods of curbing the rise and spread of these kinds of multidrug-resistant germs in animal husbandry.

When does a germ start to be considered multidrug-resistant, anyway? “As a general rule, bacteria that are resistant to at least three different classes of antimicrobial active ingredients are said to be multidrug-resistant,” says Stefan Schwarz, a professor of microbiology and, since October 2016, head of the Institute of Microbiology and Epizootics at Freie Universität. “Only acquired resistance counts for this classification,” he adds.

Alongside acquired resistance, there is also natural resistance stemming from the structure or metabolism of the respective bacteria. Bacteria that do not have a cell wall, for example, always exhibit natural resistance to active ingredients that impede the formation of a cell wall.

Antibiotics Should Be Used on a Targeted Basis

The root causes behind the rise of multidrug-resistant germs are incorrect use of medications and improper prescription practices for both humans and animals. Antimicrobial active ingredients were previously used in animal husbandry not only to fight disease, but also to boost yield.

This practice has been prohibited throughout the EU since 2006. A veterinarian’s prescription is always required for antibiotics intended for use in animals. “When antibiotics are used, people should take care to ensure that the active ingredient is tailored as closely as possible to the pathogen they are trying to fight, and that this is verified by an antibiogram,” Schwarz explains.

To perform this kind of test of antimicrobial sensitivity, samples are taken from the affected animals, and the bacteria they contain are isolated. This makes it possible to determine which bacteria are responsible for the illness. Antibiograms are then prepared for these bacteria, providing information on the active ingredients to which the bacteria are sensitive or resistant.

“This kind of precision diagnosis also helps to reduce the risk that multidrug-resistant strains of germs will arise because it makes it possible to use antibiotics on a more targeted basis,” Schwarz says. This is because depending on the type of animal and the herd size, veterinary practices for administering antibiotics vary. For dogs, cats, horses, pigs, and cattle, it is possible to treat a single animal, but turkeys and chickens being raised for food are treated collectively, by adding the medications to their feed and water. “Individually medicating a single animal is impossible if there are several thousand living in the same pen or barn,” Schwarz says.

In poultry farming, the simple fact that many animals live together in close quarters means that many more germs are transmitted from one animal to another than is the case for other animals, such as pigs or cattle. This was the impetus for forming the EsRAM research alliance.

EsRAM stands for “Development of Reduction Measures for Antibiotic-resistant Pathogens in Poultry.” It is a cooperative initiative coordinated by the Institute of Animal and Environmental Hygiene at Freie Universität with the participation of Giessen University, the University of Leipzig, the Leibniz Institute for Agricultural Engineering and Bioeconomy in Potsdam’s Bornim district, the German Federal Institute for Risk Assessment, and the Friedrich Loeffler Institute in Jena, along with the Central Association of the German Poultry Industry (Zentralverband der Deutschen Geflügelwirtschaft) and two pharmaceutical companies.

Prior studies laid the theoretical groundwork; the next step is practical implementation. “Our goal is to develop measures to prevent the rise and spread of multidrug-resistant germs in poultry farming, and to do so at every stage of production – from brooding to slaughtering,” says Uwe Rösler, a professor of animal and environmental hygiene at Freie Universität and the coordinator of the EsRAM research alliance.

This is because the different stages in animals’ lives play a crucial role, as studies have demonstrated. Rösler and his team have shown that many animals become infected with multidrug-resistant bacteria in part because germs can be passed to these animals due to certain hygienic conditions at various stages of their lives.

This means that one key issue is that animals can be infected repeatedly with the resistant bacteria, which can then multiply rapidly and with ease, unlike non-resistant bacteria, in cases where antibiotic treatment is needed.

After all, when antibiotics are administered, only the bacteria that are sensitive to them are killed off or kept from multiplying. This gives rise to an imbalance in the bacteria population, with resistant bacteria accounting for a growing proportion.

As early as during brooding, for example, the parents spread resistant bacteria to the eggs. Specific disinfection measures are taken at hatcheries to prevent chicks from being infected.

Promoting “Good” Bacteria in Animals’ Digestive Tracts

Another critical point is the farms themselves, Rösler says. While they are cleaned and disinfected thoroughly once the whole group of animals has gone to the slaughterhouse, it is often the case that bacteria survive disinfection and then infect the new animals brought into the facility.

“The goal is to start at these points and develop more effective hygienic measures,” he explains. But the most critical point, Rösler says, is still the slaughtering process. “The problem of cross-contamination, in which bacteria are transmitted from infected animals that have been slaughtered to other slaughtered animals, basically always exists,” he explains.

The risk of infection is especially high for poultry because the slaughtering process involves repeated uses of water and complex machines such as those used to scald and pluck the birds. Plucking, for example, often injures the skin slightly, and the water that is used is a perfect mechanism for spreading resistant germs.

With this in mind, the group plans to study different plucking and scalding processes, among other things, to determine which ones pose the lowest risk of contamination. The same is true of the processes by which the freshly slaughtered animals are subsequently refrigerated – here, too, the idea is to prevent cross-contamination wherever possible.

The researchers involved in the EsRAM research alliance are also pursuing another approach at the same time: They plan to promote the growth of “good” bacteria in animals’ digestive tracts, keeping resistant pathogens from getting the chance to become established there in the first place.

To that end, they are developing what are known as “competitive exclusion” (CE) cultures: natural communities of bacteria that are established in the digestive tracts of day-old chicks, occupying this environment to such a great extent that there is no room left for resistant pathogens.

Animals whose digestive systems are colonized by this kind of culture would therefore be significantly less susceptible to the establishment of colonies of resistant pathogens. Previous CE cultures are typically gleaned from the cecum of adult animals, and because they are not standardized, they are not currently approved for use in the EU. EsRAM’s goal now is to develop standardized, effective CE cultures that can also be used within the EU.

But the resistance research being performed at Freie Universität is not limited solely to the area of poultry farming. Schwarz is currently studying macrolide resistance among pathogens responsible for respiratory infections in cattle.

Macrolides are antimicrobial active ingredients that impede the formation of proteins in the bacteria, thereby inhibiting bacterial growth. Macrolide resistance is already found in these kinds of pathogens in cattle in North America. As part of a project funded by the German Research Foundation (DFG), Schwarz’s team plans to investigate the mechanisms of resistance in hopes of being able to prevent or fight the formation of resistance in Europe in a timely manner.

The working group is also involved in other international projects, including one research project that is studying the transmission of multidrug-resistant bacteria between dogs, cats, and their owners.

To advance research on the emergence and prevention of drug resistance, Freie Universität is currently establishing the Center for Resistance Research in Veterinary Medicine (TZR) at the Department of Veterinary Medicine. The new center is to pool together scientific projects on this subject.

The center was approved in June 2014 by the German Joint Science Conference (GWK), which is supported by the German federal and state governments. It will receive 28.4 million euros in funding. “This will give us excellent opportunities for research,” Schwarz says.

Rösler, the current coordinator of the Center for Resistance Research in Veterinary Medicine, is also looking forward to the new institution: “Once the center is in place, we will be the only facility in Germany that is able to study the emergence of resistance in bacteria, parasites, and viruses in various livestock and pet species on a comparative basis,” he explains. The future research center and the already broad-based research being conducted at the university today should help to curb the spread of multidrug-resistant germs among animals on a lasting basis.

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