Antimicrobial Use in Livestock

Reasons for Antimicrobial Use in Livestock

• Therapeutic use treats clinical disease in livestock.
• Prophylactic use prevents disease in high-risk livestock, acting as a drug to keep animals healthy.
• Metaphylactic use treats an entire livestock group when some animals exhibit clinical signs.
• Historically, antimicrobials were used for growth promotion, but this practice is now restricted or banned in many regions.

Therapeutic Antimicrobial Use

• Involves administering drugs to sick livestock with confirmed or strongly suspected bacterial infections.
• The goal is to eliminate pathogens and restore the animal's health.
• Veterinary diagnosis and appropriate antimicrobial selection are necessary for treatment.

Prophylactic Antimicrobial Use

• Given to healthy livestock during high-risk periods such as post-weaning or transport stress to prevent infection.
• Use of antimicrobials must be time-limited and risk-based.
• Aids in reducing major disease outbreaks.

Metaphylaxis for Cattle

• Metaphylaxis is the practice of treating an entire group/herd when some individuals show clinical signs.
• Metaphylaxis is commonly used with bovine respiratory disease (BRD) control.
• This practice is helpful to prevent disease spread in closely confined groups such as feedlots.

Popular Antimicrobial Classes

• Beta-lactams (penicillin, cephalosporins)
• Tetracyclines
• Macrolides
• Fluoroquinolones
• Sulfonamides
• Aminoglycosides.

Beta-Lactams Mechanism

• Inhibits bacterial cell wall synthesis by binding penicillin-binding proteins.
• Spectrum varies: from narrow to broad, often effective against Gram-positive bacteria.
• Examples include Penicillin G, Ampicillin, and Ceftiofur.
• Withholding times and extra-label usage restrictions should be taken into account including for cephalosporins .

Tetracyclines

• This class of antibiotic inhibits protein synthesis by binding to the 30S ribosomal subunit.
• Broad-spectrum, effective against a range of Gram-positive, Gram-negative, and atypical organisms.
• Used for respiratory diseases, some enteric infections, and reproductive pathogens.
• High-levels of widespread resistance and cost-effectiveness are critical considerations.

Macrolides

• Inhibits protein synthesis by binding to the 50S ribosomal subunit.
• It is primarily effective against Gram-positive and some Gram-negative bacteria; it is excellent for respiratory pathogens.
• Examples include Tylosin, Tilmicosin, and Tulathromycin.
• When using in feedlots for metaphylaxis, handling and dosage guidelines must be closely followed.

Fluoroquinolones

• Mechanism: inhibits DNA gyrase/topoisomerase, which blocks DNA replication.
• Broad-spectrum, including Gram-negative, some Gram-positive, and mycoplasma.
• Enrofloxacin is a common example.
• Critically important for human medicine and restricted extra-label use must be considered.

Phenicols

• Inhibits protein synthesis by binding to the 50S ribosomal subunit.
• It is broad in spectrum and effective against many Gram-positive, Gram-negative, and some atypical organisms.
• An example of this class is florfenicol (Nuflor®).
• Keep in mind Chloramphenicol is banned in food animals in many countries; florfenicol is permitted.

Aminoglycosides

• The mechanism of aminoglycosides involves binding irreversibly to the 30S ribosomal subunit, inhibiting protein synthesis.
• The spectrum shows strong activity against many Gram-negative bacteria; there is synergy with beta-lactams for some Gram-positives.
• Examples in the class include Gentamicin and Neomycin.
• Considerations to make are nephrotoxicity and ototoxicity risks; usage in food animals is often restricted.

"Why or Why Not" - Considerations for Antimicrobial Use

• Antimicrobials may prevent illness, improve animal welfare, and ensure productivity.
• Antimicrobials may create potential residues, cause public health concerns, and promote resistance.

How to Select the Right Antimicrobial

• Clinical assessment: Evaluate clinical signs and patient's history; formulate a differential diagnosis.
• Diagnostic testing: Obtain samples for culture & sensitivity (C/S); use empirical therapy when immediate treatment is critical.
• Interpretation of results: Match the organism's susceptibility profile to available antimicrobials and consider local resistance patterns.
• Drug considerations: Pharmacokinetics, the infection site, drug safety, and withdrawal times in food animals must be taken into account when considering use. – Judicious Use: whenever possible, prescribe narrow-spectrum agents and when no other alternatives exist, reserve drugs which are critically important.

Introduction to Antimicrobial Resistance (AMR)

• AMR occurs when bacteria can survive and grow despite antimicrobial presence.
• AMR is a global priority impacting both human and animal health.
• AMR is a real threat to the effectiveness of current treatments.

Why Antimicrobial Resistance Matters

• Reduced treatment options result in higher morbidity/mortality.
• Potential for zoonotic transfer of resistant organisms.
• There can be economic impacts on producers and public health costs.

Mechanisms of Resistance

• Enzymatic degradation: Beta-lactamases, etc.
• Efflux pumps: Pump antimicrobials out of bacterial cells.
• Altered targets: Changes in ribosomal binding sites.
• Reduced permeability: Alteration of porin channels.

Enzymatic Degradation Specifics

• Bacteria produce specific enzymes that chemically modify or break down antibiotics, preventing them from binding to their target.
• An example of this mechanism, beta-lactamases hydrolyze the beta-lactam ring in penicillins and cephalosporins.
• Extended-spectrum beta-lactamases (ESBLs) also transform effective antibiotics to ones which are non-effective.

Efflux Pumps

• Efflux pumps are transmembrane proteins that actively transport antibiotics (and other toxic substances) out of bacterial cells
• By lowering the intracellular concentration of antimicrobials, these pumps prevent the drug from reaching sufficient levels to inhibit or kill the bacteria.
• Efflux pump systems are often nonspecific. Efflux pumps can remove multiple types of antibiotics, leading to multi-drug resistance.

Altered Targets

• Altered targets occur when a mutation or gene acquisition alters the shape or structure of the site where an antibiotic normally binds.
• Examples include resistance to Staphylococcus aureus (MRSA).
• Altered or changed ribosomal proteins or rRNA can prevent macrolides, tetracyclines, or aminoglycosides from binding, leading to resistance.

Reduced Permeability

• Reduced permeability occurs through changes in porin proteins in the outer membrane of Gram-negative bacteria.
• When porin channels become fewer in number or have altered structure, entry of certain antibiotics (especially hydrophilic ones like beta-lactams) into cells is inhibited.
• Synergistic effects in combination with other resistance strategies exist for overall resistance enhancement.

United States Regulatory Agencies

• FDA (Food and Drug Administration): Approves veterinary drugs, labeling, and new regulations.
• USDA (U.S. Department of Agriculture): Oversees food safety and monitors drug residues.
• EPA (Environmental Protection Agency): Addresses environmental impacts like manure management.
• State Veterinary Boards: Enforce veterinary practice standards.

Veterinary Feed Directive (VFD)

• The concept originated when the FDA noticed widespread, unregulated use of medically important antimicrobials in feed was increasing antibiotic resistance.
• FDA finalized rules between 2015 and 2017 to ensure veterinary oversight of feed-based antimicrobials.
• When deemed "medically important” by the FDA, antimicrobials can only be used in feed with a order from a vet.
• A order from a vet ensures vets know the operation, the animals and can prescribe medications.

VFD Implementation

• Producers and veterinarians need to work on strengthening their relationship to obtain timely orders for medicated feed.
• This collaborative effort will help improve overall herd health and lessen the reliance on antimicrobials
• One of the main difficulties from VFD implementation is the education of smaller farms that may not have easy access to veterinary services.

New Regulations

• The new label requirements stemmed from the recognition that widespread availability of certain antibiotics without veterinary supervision was likely lead to accelerated resistance.
• Veterinary supervision allows the correct drugs to be prescribed appropriate for the condition of the animals.
• In order to combat this the FDA issued Guidance for Industry (GFI) #263 requiring sponsors to revise labeling, implemented in June 2023 stating that products OTC can only be sold without a valid script.
• As such the new regulations affect “medically important” antibiotics—those also used in human medicine impacting feed store and agriculture sales
• Among these drug classes are drugs for Penicillin G, oxytetracycline, various sulfa drugs, and some macrolides/lincosamides that now require scripts

Surveillance Systems

• NARMS (National Antimicrobial Resistance Monitoring System) is an entity that tracks Salmonella, Campylobacter, E. coli in animals and in humans.
• WHO, OIE/WOAH are others engaged data collection.
• There has been an increase in the Importance of ongoing sample testing and the desire to monitor the patterns of resistance.

One Health Approach

• The One Health concept stresses the interconnectedness of the sectors of human, animal, and environmental health.
• Coordination and information sharing on shared pathogens, resistance genes, transmission across species, and ecosystems.
• Action taken should include, coordinated surveillance, research,and policy with sustainable solutions.

Minimizing Resistance

• Develop treatment protocols and standard operating procedures (SOPs).
• Emphasizing diagnostic testing, specifically culture and sensitivity can reduce the rate of AMR.
• Keeping accurate records of antimicrobial usage.
• Improving biosecurity, nutrition, and management and exploring using other drug classes to improve resistance.

Consequences of Ignoring AMR

• Ignoring AMR can cause treatment failures in both livestock and humans.
• Ignoring AMR can cause increased animal welfare concerns.
• Ignoring AMR can lead to restrictions in trade/export due to residues or resistant strains being found.
• Ignoring AMR an erode public perception and thus consumer trust.

Veterinarian's Role in AMR Prevention

• Responsible antimicrobial prescribing is important.
• Producers must be educated on proper dosing, administration, and withholding periods.
• Being open to collaboration among stakeholders is very important for One Health.