Hot topics: Antimicrobial resistance

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“Resistance has been a problem since we discovered antibiotics,” said Jenifer Chatfield, DVM, DACZM, DACVPM, during her session on antimicrobial resistance at the recent Fetch dvm360® Virtual Conference. During her lecture, she discussed the development of antimicrobial resistance and how veterinary practitioners can work to be part of the solution.

Antimicrobial resistance is not new

Understanding the history of antimicrobial resistance is important as we begin to look for solutions to the problem. Although many view antimicrobial resistance as a more recent public health threat, Chatfield said, “It did not come about during your career.”

“Almost as soon as we develop an effective antibiotic, resistance develops,” she said. It has been recognized by scientists since early in the use of antimicrobials. Sir Alexander Fleming’s 1945 Nobel Prize acceptance speech included, “One note of warning…it is not difficult to make microbes resistant to penicillin.” Initially, the discovery of new antibiotics outpaced resistance, but now that antibiotic development has slowed, resistance is recognized as a bigger problem.

Mechanisms of resistance

The first step to combating antimicrobial resistance is understanding how resistance develops. First, Chatfield emphasized the difference between persistence and resistance: “Just because a bacterium persists in the face of an antibiotic does not mean it is resistant.” Persistent cells often survive because they are in a dormant phase and do not pass resistant genes on to their daughter cells, so new growth will remain susceptible to the antibiotic.

Antimicrobial resistance can be natural or acquired. Natural resistance is often intrinsic, which indicates a bacterial species has an innate characteristic that gives it resistance to certain classes of antibiotics. For instance, β-lactams and cephalosporins work by inhibiting cell wall synthesis. Any bacterial species lacking a cell wall, such as Mycoplasma, possesses intrinsic resistance to these classes of antimicrobials.

This type of resistance is present independent of previous exposure to antibiotics and does not develop through horizontal gene transfer. Chatfield likens intrinsic resistance to “a genetic lotto that the bacteria won that gives them some characteristic that makes them resistant to an antibiotic.” As our knowledge of bacterial species has increased, so has our understanding of intrinsic resistance. Knowing the antibiotics to which a bacterial species is intrinsically resistant can aid practitioners in appropriate antimicrobial selection before the results of sensitivity testing are available. A summary chart of known intrinsic resistance for some common bacterial species is available.¹

Although intrinsic resistance requires no effort on the part of the bacteria, acquired resistance requires genetic material to be passed between bacteria through horizontal gene transfer. Bacteria have 4 main mechanisms of antibiotic resistance:

• Limiting uptake of a drug through the intrinsic characteristics of the cell wall or outer membrane
• Inactivating drugs after entry into the cell through degradation or chemically altering the drug, such as through hydrolyzing it
• Modifying the drug target by changing the number or type of receptors expressed on the cell surface
• Expressing efflux pumps that eject the drug outside the cell once it enters

It is important to remember that not all bacteria that possess resistant genes will express them. In some cases, the cell must have an environmental stressor, such as lack of nutrients or a change in pH to express the drug resistance. Additionally, in many cases there is a trade-off for the bacteria when they express or acquire resistance. For instance, methicillin-resistant Staphylococcus aureus (MRSA) do not grow as quickly as nonresistant Staphylococcus aureus. Bacteria always try to evade things that are trying to kill them, and Chatfield says the presence of resistance does not “mean that the vet, the client, or the pet have done anything wrong.”

Tools to combat resistance

“It is an inevitability that resistance is going to develop,” Chatfield said. One of the challenges physicians and veterinarians face when using antibiotics is that “anyone who is using antibiotics is contributing to the development of resistance.” We must use antibiotics in many cases, but Chatfield emphasizes that “we do know that we can [use them] better.”

The use of culture and sensitivity in practice is encouraged by many veterinary guidelines.² Despite this, a 2015 survey of veterinarians in the state of Washington found that 24% of respondents reported never ordering culture and sensitivity in practice.³ Of the 76% of respondents who reported utilizing culture and sensitivity testing, 36% stated they used it often or always when treating presumptive bacterial infections.³

Chatfield knows there are barriers to using culture and sensitivity in practice. Cost is one of the top factors reported by many veterinarians.³ Additionally, culture results can take several days or even weeks to return depending on the organism. In some cases, patients need treatment before these results are available. Chatfield has also seen that cultures can be unreliable, especially in viral infections or those with multiple pathogens.

Molecular diagnostics offer a faster, more reliable tool for detecting microbial infections. Quantitative polymerase chain reaction (qPCR) allows for amplification of genetic material present in a sample. The results of qPCR can be used to identify pathogens and determine the amount of the pathogen present. Because results of each cycle are seen in real time, the first microbe identified is the one that was present in the largest quantity in the original sample.

In addition, qPCR can guide treatment by helping to determine sensitivity for the identified pathogens. Many genes for acquired resistance are known and the presence or absence of these genes can be assessed using qPCR. These results, combined with our knowledge of intrinsic resistance of bacterial groups, guide antimicrobial treatment.

Chatfield discussed many advantages of using molecular diagnostics over culture and sensitivity. They have higher sensitivity and specificity. Results are available more rapidly, usually within 24 to 48 hours of sample collection. Additionally, these diagnostics can allow identification of bacteria, viruses, and fungal organisms from the same sample, allowing better identification of coinfections.

Looking to the future

“We are headed in a direction in veterinary medicine where we will be able to effectively say that we can…take steps to combat antimicrobial resistance development,” Chatfield said. Molecular diagnostics are becoming increasingly available and affordable. She encourages practitioners to offer these diagnostics to clients and discuss the advantages of using them. Although clients may decline the testing, we should be offering it, she said. Ultimately, we cannot prevent the development of antimicrobial resistance but we can slow its pace using molecular diagnostics to guide our use of antimicrobials.

References

1. Reygaert WC. An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol. 2018;4(3):482-501. doi:10.3934/microbiol.2018.3.482
2. Weese JS, Blondeau JM, Boothe D, et al. Antimicrobial use guidelines for treatment of urinary tract disease in dogs and cats: antimicrobial guidelines working group of the international society for companion animal infectious diseases. Vet Med Int. 2011;2011:263768. doi:10.4061/2011/263768
3. Fowler H, Davis MA, Perkins A, et al. A survey of veterinary antimicrobial prescribing practices, Washington State 2015. Vet Rec. 2016;179(25):651. doi:10.1136/vr.103916

Kate Boatright, VMD, a 2013 graduate of the University of Pennsylvania, is a practicing veterinarian, freelance speaker, and author in western Pennsylvania. She is passionate about mentorship, education, and addressing common sources of stress for veterinary teams and recent graduates. Outside of clinical practice, she is actively involved in organized veterinary medicine at the local, state, and national levels.