MADISON, Wis. – The inability to treat an infectious disease, whether in humans or animals, is a scary thought. This becomes a reality when bacteria prove resistant to certain antibiotics.
Bacteria reproduce rapidly. And over time, bacteria have learned how to outsmart antibiotics. Extensive use of an antibiotic can lead to bacteria becoming resistant to its effects, clearing the path for various infections or diseases to gain footing.
“Antibiotic resistance was discovered only 85 years after using the first effective antibiotic,” said Dr. Mike Apley, DVM, professor of veterinary clinical sciences at Kansas State University College of Veterinary Medicine. “When there’s a mutation that confers resistance to an antibiotic, the use of that antibiotic in that population can select for those with that mutation. The genetic components that made up the mutation can be transferred not only within specie but between gender and sometimes within the family of bacteria. It’s really dramatic how it can move through a population.”
Apley’s presentation, “Impacts of Antibiotic Resistance,” during the Professional Dairy Producers of Wisconsin Virtual Business Conference March 19 explored the history of antibiotic groups and the role resistance plays in food animal production and human health.
The Centers for Disease Control and Prevention estimates more than 2.8 million antibiotic-resistant infections occur in the United States each year, resulting in more than 35,000 deaths. In addition, there were an estimated 223,900 cases of Clostridioides difficile in 2017 and at least 12,800 of these cases died. C. diff is a bacterium that can cause symptoms ranging from diarrhea to life-threatening inflammation of the colon and usually occurs after using an antibiotic.
Agriculture gets tagged in many conversations about antibiotic resistance because it is an industry that produces food for people. Concern surrounding the use of antibiotics in food animals is founded on the premise that a resistant organism could be released into the environment or somehow survive processing and end up inside the body.
Antibiotics have come a long way since the days of using crude treatments like arsenic derivatives or mercury cream to wipe out a bacterial infection. Sulfas were invented in 1935, and in 1942, penicillin was created. The first tetracycline (chlortetracycline) was released in 1948 and used extensively in both animals and humans. A burst of antibiotics came on the scene in the 1940s and 1950s as new groups were added, such as chloramphenicol, neomycin, erythromycin, vancomycin and virginiamycin. In 1985, carbapenems were introduced. These, used for hyper-resistant organisms, are used on the human side but not in food animal medicine.
Since 1985, a couple major groups have emerged for use in human medicine. However, food animal production has not seen a new group of drugs come through since 1978 when the fluoroquinolone group came into being. At that time, they were used only in people. Members of that group today are known as enrofloxacin and danofloxacin. Enrofloxacin could be used in a replacement heifer, but there are no fluoroquinolones labeled for use in lactating dairy cows.
“It’s been 42 years since animal production has seen a new group of antibiotics,” Apley said. “And the likelihood of a new group being released for extensive use in animals is minimal.”
A pathogen is either susceptible or resistant to antibiotics. One that is susceptible will respond to treatment with antibiotics. And one that is resistant will not respond; the antibiotic will have no effect.
How quick does resistance happen? The first clinical use of penicillin occurred in 1942. By 1949, the first resistant staff bacteria showed up. Ampicillin began use in 1962, and in 1966, bacteria resistant to the drug were found. Cefotaxime was invented in 1979 and showed resistance by 1985. That same year, carbapenems were introduced with first resistance occurring in 1993. Many times, it took only four to seven years from when the drug was first released to its first resistant organism being detected.
Whether talking about a mastitis pathogen, a pneumonia pathogen, an E. coli from a calf with scours, or an organism from foot rot, one can look at the concentration of drug required to kill the bacteria. When bacteria are inhibited at a low dose of medicine, such as 0.06 or 0.12 micrograms per milliliter, that means it is susceptible to the antibiotic. Whereas, if it takes 8, 16 or 32 micrograms/ml, this means the population is resistant and associated with a resistant gene or genes.
When an antibiotic is first in use, a large amount of the population requires a low concentration to inhibit the bacteria. As time passes, more bacteria break away, and after years of extensive use, there might be a group that is resistant. Bacteria can become dominant when placed under the pressure of an antibiotic. If it continually receives that pressure, even intermittently, it can select for the resistant ones in that population, and they can become dominant.
“Mutations occur that allow for resisting the effect of this antibiotic,” Apley said. “And as we apply selective pressure on a population, we’ve now selected for more and more of those to be present.”
Resistance does not necessarily mean there is no effective treatment for the infection. Rather, it means a different antibiotic will need to be used, and multiple drugs may have to be tried before a winner is found. However, waiting too long to intervene on an infectious disease could lessen the chances of a good outcome. The veterinarian and producer should work together to dig out evidence that a drug will work.
Antibiotic resistance can force the use of more dangerous choices. Desperate measures to find an antibiotic that works when no other option does has led to using a drug called colistin in humans, which is highly toxic to the kidneys in some cases.
Organisms pertaining to the dairy industry that are rated as a serious resistance threat include drug-resistant non-typhoidal salmonella, which can come through the food chain via meat but rarely does. Extended spectrum ß-lactamase producing Enterobacteriaceae, such as salmonella and E.coli, is another resistant organism documented in food animals. Salmonella Newport is a bacteria that can occur in cattle and one that shows some serious resistance. Apley said it is a very aggressive pathogen when it gets turned loose and can often be fatal.
Mannheimia haemolytica is one of the primary respiratory pathogens found in dairy and beef cattle with pneumonia. It is a dominant pathogen that is resistant to ampicillin, enrofloxacin, gentamicin, penicillin, spectinomycin, tilmicosin and more. It does, however, show susceptibility to ceftiofur and florfenicol.
The use of antimicrobial drugs in food producing animals is decreasing. Sales of these drugs dropped 30% from 2016-18. Tetracyclines, which represent the largest volume of domestic sales in food producing animals with usage split evenly between the dominant users of cattle and swine, decreased in use by 40% from 2016-17. Fluoroquinolones and cephalosporins are critically important human drugs that comprise a small portion of use in food animals.
The Food and Drug Administration has a five-year action plan for antibiotic use in food production animals, which includes promoting antimicrobial stewardship and enhancing processes to support product development. Under this plan, the FDA would like to bring all dosage forms of medically important antimicrobial drugs approved for use in food-producing animals under the oversight of a licensed veterinarian. Apley predicts that by the end of 2022, the industry will see the removal of all over-the-counter antibiotic labels as they are replaced by prescription labels.
Failure to prevent infection is the first failure of antibiotic stewardship, Apley said. The second failure is the failure to appropriately treat the infection with an effective antibiotic. And the ultimate antibiotic failure is bacterial population exposure without achieving the desired effect.
“Those are the things we try to prevent as we pursue antibiotic stewardship and preserve the ability to have these valuable tools,” Apley said.  
Apley believes the biggest area of vulnerability for the dairy industry is the use of antibiotics for prevention and control.
“I think we have a lot of uses that are certainly justified due to disease pressures we see and the fact we’ve demonstrated these to be effective,” Apley said. “But there’s going to be public conversations about why we need to use them for this reason. For example, there’s a lot of discussion about blanket dry cow therapy versus selective dry cow therapy.”  
How can the industry work together to shape the future for responsible use of antibiotics?
“We need to continue to be open and transparent in all the ways we try to control diseases,” Apley said. “We need to make sure we have protocols in place when we use antibiotics, and that we monitor their outcome and continue to evolve in our sophistication and recordkeeping. We’ve come a long way, but we still have a long way to go.”