The author is in the Department of Clinical Sciences, Kansas State University, Manhattan. This article is part of a series being prepared in cooperation with the American Association of Bovine Practitioners.
Antimicrobial resistance is the inability to successfully treat an infection because the bacteria causing the disease are not susceptible to the effects of the antibiotic. It is considered one of the most critical public health issues of the 21st century.
It is significant that legislators are becoming concerned that antimicrobial use in livestock can contribute to the emergence and spread of resistance bacteria in humans. These concerns were recently manifested in the Preservation of Antimicrobials for Medical Treatment Act (PAMTA) introduced into the U.S. House (H.R. 1549) and Senate (S. 619). The bills require the FDA to re-review the approvals it previously issued for seven classes of antibiotics considered important to human medicine and that currently are used in animal feed for so-called "nontherapeutic" uses. Any that fail to meet the criteria of having a "reasonable certainty of no harm" from a resistance point of view will have their approvals rescinded.
It is troubling that a definition of "reasonable certainty" is not provided. If the bill passes, the dairy industry may face restrictions on the availability and use of medicated milk replacers.
What makes bacteria resistant?
First, the structural characteristics of a bacteria species may make them repel the effects of an antibiotic. For example, beta-lactams (penicillin, ampicillin, and ceftiofur) destroy bacteria by binding to protein targets in the bacteria cell wall. This causes the cell wall to become defective and the bacteria to burst.
Furthermore, because beta-lactams disrupt cell wall development they work best against rapidly dividing bacteria. So if the bacteria are not growing and reproducing, they may not respond to treatment with penicillin or ceftiofur.
We may inadvertently create this situation if we treat cattle with a combination of drugs that prevent bacteria from multiplying (for example, oxytetracycline) and that require multiplying bacteria for maximum efficacy (for example, penicillin). So, even though we may think that two antibiotics should work better than one, this may not be the case.
The second kind is called "acquired resistance." Bacteria can acquire resistance either through mutation of their own genetic material or through the transfer of genetic material from one organism to another. The first mechanism allows bacteria to produce enzymes that inactivate the antimicrobial. This mechanism commonly is seen in bacteria that become resistant to beta-lactams and is especially prevalent in Staphylococcus spp. The second mechanism involves changes in the permeability of the bacteria that make it harder for the antimicrobial to enter the organism.
A third mechanism involves the expression of so- called "efflux pumps" that allow the bacteria to actively "pump" the drug out of the organism. Efflux pumps reduce the concentration of the drug inside the cell so it stays below a level required to have an effect. This is common with oxytetracycline.
A fourth resistance mechanism is when the drug target in the bacteria is altered so that the antimicrobial can no longer bind to it. This mechanism especially is common among bacteria that become resistant to beta-lactams.
Transfer of resistance elements between bacteria is considered the most important contributor to resistance.
Studies conducted at Sanjeev Narayanan's laboratory at Kansas State University have shown that the presence of antimicrobials and stress hormones can actually raise the rate of resistance transfer between certain strains of resistant and susceptible bacteria in the lab. To be sure, bacteria did not develop all resistance in response to the use of antimicrobials. Many of the resistance mechanisms we encounter survived because they gave the organism a competitive advantage. In fact, many of the antimicrobials in widespread use today were derived from mold in the soil suggesting that the process of resistance selection has been around for centuries. However, the concern is that the more we depend on antimicrobials and the more widespread their use, the more likely it is that we may be adding to the selection pressure on bacterial populations resulting in the emergence of more resistant bacteria or a greater proportion of bacterial populations with pre-existing resistance characteristics.
Another concern is that bacteria in the gut of a treated animal may be exposed inadvertently to the drug even though these organisms usually are not the target of therapy. The selection pressure provided by this exposure may select for resistant bacteria that could, in turn, contaminate the carcass at slaughter and pose a risk to the consumer. Nonspecific selection of resistant bacteria in the gut and subsequent food safety concerns may, therefore, be an unintended consequence of antimicrobial use in food animals.
How do we measure bacterial susceptibility and resistance?
Laboratory identification of bacteria requires growth of the organism on nutrient-rich media followed by identification of the organism based on growth or structural characteristics. Bacteria grown in a laboratory may be subjected to tests to determine their susceptibility to antimicrobials. Typically, bacterial isolates are cultured in the presence of doubling concentrations of antimicrobials until a drug concentration is found that inhibits visible growth. This antimicrobial concentration is called the minimum inhibitory concentration or MIC. This information may be invaluable to your veterinarian as this will help with selecting a suitable drug and determining an appropriate dose and duration of therapy.
Bacteria that continue growing in the presence of antimicrobial concentrations higher than concentrations that are achievable in the animal using normal dosing schedules are considered resistant. In this case, we physically cannot get enough antimicrobial in the animal to achieve the concentrations required. Although susceptibility testing is not an exact science, it does provide information that may be critical to your veterinarians and will help you formulate a course of action that will maximize the chances for a favorable treatment outcome.
What could this mean to me?
When cattle fail to respond to antimicrobial therapy, it does not necessarily imply that they were infected with an antimicrobial-resistant bacteria. Equally, if they are infected with a resistant organism, it does not mean that the animal will not recover, although this category does imply that the antimicrobial will not assist in the recovery because the achievable systemic concentrations of the drug will be lower than the MIC of the causative organism.
It is critical that you identify sick animals as early as possible in the course of infection and to develop appropriate treatment protocols in consultation with your veterinarian. It also is important to keep records of which animals received treatment and to regularly review treatment outcomes with your vet.
Finally, as an industry, we have an obligation to try to restrict use of antimicrobials for the treatment of animals that are most likely to respond to treatment. We also should develop vaccination and biosecurity programs and improve hygiene to reduce the number of animals requiring antimicrobial therapy on our farms.
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Antimicrobial resistance is the inability to successfully treat an infection because the bacteria causing the disease are not susceptible to the effects of the antibiotic. It is considered one of the most critical public health issues of the 21st century. It is significant that legislators are becoming concerned that antimicrobial use in livestock can contribute to the emergence and spread of resistance bacteria in humans. These concerns were recently manifested in the Preservation of Antimicrobials for Medical Treatment Act (PAMTA) introduced into the U.S. House (H.R. 1549) and Senate (S. 619). The bills require the FDA to re-review the approvals it previously issued for seven classes of antibiotics considered important to human medicine and that currently are used in animal feed for so-called "nontherapeutic" uses. Any that fail to meet the criteria of having a "reasonable certainty of no harm" from a resistance point of view will have their approvals rescinded.
It is troubling that a definition of "reasonable certainty" is not provided. If the bill passes, the dairy industry may face restrictions on the availability and use of medicated milk replacers.
What makes bacteria resistant?
First, the structural characteristics of a bacteria species may make them repel the effects of an antibiotic. For example, beta-lactams (penicillin, ampicillin, and ceftiofur) destroy bacteria by binding to protein targets in the bacteria cell wall. This causes the cell wall to become defective and the bacteria to burst.
Furthermore, because beta-lactams disrupt cell wall development they work best against rapidly dividing bacteria. So if the bacteria are not growing and reproducing, they may not respond to treatment with penicillin or ceftiofur.
We may inadvertently create this situation if we treat cattle with a combination of drugs that prevent bacteria from multiplying (for example, oxytetracycline) and that require multiplying bacteria for maximum efficacy (for example, penicillin). So, even though we may think that two antibiotics should work better than one, this may not be the case.
The second kind is called "acquired resistance." Bacteria can acquire resistance either through mutation of their own genetic material or through the transfer of genetic material from one organism to another. The first mechanism allows bacteria to produce enzymes that inactivate the antimicrobial. This mechanism commonly is seen in bacteria that become resistant to beta-lactams and is especially prevalent in Staphylococcus spp. The second mechanism involves changes in the permeability of the bacteria that make it harder for the antimicrobial to enter the organism.
A third mechanism involves the expression of so- called "efflux pumps" that allow the bacteria to actively "pump" the drug out of the organism. Efflux pumps reduce the concentration of the drug inside the cell so it stays below a level required to have an effect. This is common with oxytetracycline.
A fourth resistance mechanism is when the drug target in the bacteria is altered so that the antimicrobial can no longer bind to it. This mechanism especially is common among bacteria that become resistant to beta-lactams.
Transfer of resistance elements between bacteria is considered the most important contributor to resistance.
Studies conducted at Sanjeev Narayanan's laboratory at Kansas State University have shown that the presence of antimicrobials and stress hormones can actually raise the rate of resistance transfer between certain strains of resistant and susceptible bacteria in the lab. To be sure, bacteria did not develop all resistance in response to the use of antimicrobials. Many of the resistance mechanisms we encounter survived because they gave the organism a competitive advantage. In fact, many of the antimicrobials in widespread use today were derived from mold in the soil suggesting that the process of resistance selection has been around for centuries. However, the concern is that the more we depend on antimicrobials and the more widespread their use, the more likely it is that we may be adding to the selection pressure on bacterial populations resulting in the emergence of more resistant bacteria or a greater proportion of bacterial populations with pre-existing resistance characteristics.
Another concern is that bacteria in the gut of a treated animal may be exposed inadvertently to the drug even though these organisms usually are not the target of therapy. The selection pressure provided by this exposure may select for resistant bacteria that could, in turn, contaminate the carcass at slaughter and pose a risk to the consumer. Nonspecific selection of resistant bacteria in the gut and subsequent food safety concerns may, therefore, be an unintended consequence of antimicrobial use in food animals.
How do we measure bacterial susceptibility and resistance?
Laboratory identification of bacteria requires growth of the organism on nutrient-rich media followed by identification of the organism based on growth or structural characteristics. Bacteria grown in a laboratory may be subjected to tests to determine their susceptibility to antimicrobials. Typically, bacterial isolates are cultured in the presence of doubling concentrations of antimicrobials until a drug concentration is found that inhibits visible growth. This antimicrobial concentration is called the minimum inhibitory concentration or MIC. This information may be invaluable to your veterinarian as this will help with selecting a suitable drug and determining an appropriate dose and duration of therapy.
Bacteria that continue growing in the presence of antimicrobial concentrations higher than concentrations that are achievable in the animal using normal dosing schedules are considered resistant. In this case, we physically cannot get enough antimicrobial in the animal to achieve the concentrations required. Although susceptibility testing is not an exact science, it does provide information that may be critical to your veterinarians and will help you formulate a course of action that will maximize the chances for a favorable treatment outcome.
What could this mean to me?
When cattle fail to respond to antimicrobial therapy, it does not necessarily imply that they were infected with an antimicrobial-resistant bacteria. Equally, if they are infected with a resistant organism, it does not mean that the animal will not recover, although this category does imply that the antimicrobial will not assist in the recovery because the achievable systemic concentrations of the drug will be lower than the MIC of the causative organism.
It is critical that you identify sick animals as early as possible in the course of infection and to develop appropriate treatment protocols in consultation with your veterinarian. It also is important to keep records of which animals received treatment and to regularly review treatment outcomes with your vet.
Finally, as an industry, we have an obligation to try to restrict use of antimicrobials for the treatment of animals that are most likely to respond to treatment. We also should develop vaccination and biosecurity programs and improve hygiene to reduce the number of animals requiring antimicrobial therapy on our farms.
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