What You Need to Know &Think About When Selecting Antibiotics

1. What You Need to Know &Think About When Selecting Antibiotics The objective will be to help folks better understand: 1) how antibiotics work … clinically 2) antibiotic classes … & what makes them different 3) how to think through developing treatment protocols 4) understand dose management & resistance development 5) how to select a proper antibiotic for different diseases 6) how the other things given sick cattle can influence an antibiotic's effectiveness 7) how to know when to switch 8) which antibiotic would make a better choice when a switch is need if an animal doesn't respond 9) when to quit 10) potential residue considerations & management

2. Parts of the Puzzle

3. IBR at work

4. the role of antibiotics in treating diseases caused by different bugs … focus on respiratory disease • Shipping fever / BRD … set up by lack of immune protection stress, commingling, & timing • Virus destroys cells that protect the lung … • Bacteria move from their hang out to lung • Lungs cells provide lots of food with very little defense

7. Disease sequence of events: • Susceptible animal exposed. • Incubation is the period (time) from the first replication of the disease causing biological agent until sufficient compromise of the target organ(s) occurs causing loss of function of the target organ(s). • Primary viral BRD this averages 3 days. • Secondary bacterial BRD averages 3 to 5 days behind the initial viral infection.

8. Disease sequence of events: • Inflammation occurs in stages. • Early, the body diverts white blood cells and blood in to the affected area typically causing swelling of tissue, both cells and spaces between cells. • As the inflammation continues, loss of function of the affected tissue occurs. • Late stage of inflammation is involved in the body trying to clean up, remove, or repair / reconstruct the damaged tissue. • The late stage of inflammation is the first stage of recovery. … begins 7 to 10 days … last for weeks

11. how the antibiotics work • Antibiotic – mold, 1928 • Protect molds from bacteria • No effect on viruses or normal body cells • Two types -static (slows) & cidal (kills) • Four mechanisms • Cripples cell wall • Interferes with protein synthesis • Confuses metabolic processes • Blocks DNA / RNA synthesis • Different bacteria … require different mechanisms to stop them …

12. antibiotic resistance mechanisms • Decrease Cell Wall Uptake / Perm • Aminoglycosides • Efflux • Macrolides, fluoroquinolones, tetracyclines • Enzymes Induced • Aminoglycosides, florfenicol, beta-lactams • Altered Target Binding Sites • Ribosome …macrolides, lincosamides • Wall Protein … beta-lactams, glycopeptides • DNA … fluoroquinolones • Gene Resistance • Plasmids … b-lact, tetra, macro, linco, fluro, sulfa • Transposons … beta-lactams, glycopeptides • Chromosome … beta-lactams, fluoroquinolones

16. PK / PD Relationships

17. Antibiotic Movement

21. why an antibiotic may seem to work on some sets of cattle and not others Source … Immune prep history Source … Nutritional history Source … Stress & Commingling BIGGEST FACTOR … TIMING!!! How much of a head start ??? • Animal’s ability to help fight back • Differences in bugs … Diagnosis???

22. Prevention … is key Treatment salvages only part of the loss Immune preparation Treatment timing

23. Responsible Use Considers RESIDUE AVOIDANCE

24. Antibiotic Resistance & Residue Concerns… Fuel the winds of change example: HR 1549 & S619 … “PAMTA” “Preserve Antibiotics for Medical Treatment Act” Targets ‘Nontherapeutic Use’ “with respect to a critical antimicrobial animal drug, means any use of the drug as a feed or water additive for an animal in the absence of any clinical sign of disease in the animal for growth promotion, feed efficiency, weight gain, routine disease prevention, or other routine purpose.’ ‘(A) any kind of penicillin, tetracycline, macrolide, lincosamide, streptogramin, aminoglycoside, or sulfonamide; or (B) any other drug or derivative of a drug that is used in humans to treat or prevent disease or infection caused by microorganisms.’

25. Something is going WRONG … 25 25

26. Flunixin Injection Sites … Ouch, This Has Got to HURT! • Why do we use flunixin? • Reduce Inflammation • Make them feel better? • How could causing this much tissue damage make them feel better? • Can’t give it IV … Considering the adverse effect … if it can’t be given IV why not skip its use 26

27. The National Residue Program (NRP) consists of two sampling plans: domestic &import. • The domestic sampling plan includes … Scheduled Sampling & Inspector Generated Sampling • Scheduled sampling plans consist of the random sampling of tissue from healthy appearing food animals • Statistically, applying sampling rates of 230 & 300 per production class population assures a 90 percent and 95 percent probability, respectively, to detect residue violations if the violation rate in the population is equal to or greater than one percent. 27

28. The National Residue Program (NRP) consists of two sampling plans: domestic &import. • The Tolerance or Maximum Residue Limit (MRL) for each class of compound are listed in: • Title 21 CFR for FDA regulated compounds • Title 40 CFR for EPA regulated compounds 28

29. The National Residue Program (NRP) consists of two sampling plans: domestic &import. • Inspector generated sampling is conducted by in-plant Public Health Veterinarians (PHVs) • This occurs when the in-plant PHV suspects that an animal may have violative level of chemical residues. • Targets “individual suspect animals and suspect populations of animals.” • Individuals: Target injection sites & animals with active infections that could reasonably be suspected as having been recently treated. • Populations: History of residue violations 29

30. USDA-FSIS Changes Residue Screening Test • In October 2008, the USDA Food Safety and Inspection Service (FSIS) awarded Charm Sciences a contract to provide Charm KIS Tests to USDA inspectors at slaughter facilities to screen for sulfonamides and antibiotic drugs under the National Residue Program (NRP).  • FSIS will begin implementing the Charm KIS Test in phases starting with cattle (FSIS notice 50-90) and eventually implement it for all livestock. 30 30

31. Total Cattle Marketed 31

32. Residues … Flunixin

33. Residues … Sulfas

34. Residues … Sulfas

35. Residues … What were they thinking?

36. Residues … beta lactams

37. Residues … OTC vs Vet Rx 37

38. Chemical Defects … Residues BEEF IS BEEF … & 0.000 positive % … IS NOT ZERO 1982, just under 2% of all beef cattle 2010, random samples: Zero antibiotics High Risk TARGETED Samples have residue rates that are very low! … 38

39. Flunixin Residues: • Flunixin ELDU … leading to residues • The Center for Veterinary Medicine Reminds Veterinarians to Correctly Use Flunixin Meglumine • (FDA Veterinarian Newsletter 2007, Volume XXII, Number 11) • FARAD, Flunixin WD… IM administration requires 30 days for single injection … 60 days for multiple IM injections … WD of SC flunixin meglumine in cattle cannot be established. (JAVMA 232(5):697-701, 2008.) 39

40. Ceftiofur … Under Pressure! • Ceftiofur … approved for cattle in 1988 • 20 years with no residues listed in USDA-FSIS “Red Book” reports (these are yearly residue testing reports). • FDA announced elimination of ELDU, July 2008, but amended ELDU ban after comment period evaluation. • Dr Flynn (FDA) announced ceftiofur residues at KSU meeting May 2009 … communications suggest a significant number of violative residues in 2008, … perhaps associated with test methodology changes … (2/3 in cull dairy cows associated with producers not following the prescribed usage, dosing or withdrawal time) Would “Cow-side”, residue screening help? 40

41. Vet Survey Materials & Methods (June 2007) • Postal survey (within AABP newsletter) • 27 questions • Demographics (6) • Treatment Strategies (12) • Client Communication (4) • Dairy Beef Quality Assurance Programs (5) 41

42. “How often do you look at your clients written treatment records?” Vet Survey Materials & Methods (AABP, June 2007) 42

43. “How often do you think producers will not comply with instructions & will cause a violative residue?” Vet Survey Materials & Methods (AABP, June 2007) 43

44. Ceftiofur Residues … “The Most Probable Cause” • Ceftiofur Na… the “zero” withdrawal antibiotic (CM = 14 ug/ml, T½ =10hrs, MRL= 8ug/ml) • … this led to “ownership” of the dairy market • MRL lowered to 0.4 ug/ml … WD to 4 days • Ceftiofur HCl and CCFA … • similar change in WD math • Producers not respecting new WD times • record monitoring vigilance important 44 44

45. RESIDUE AVOIDANCE … Carefully evaluate your ELDU & the extended withdrawals you assign. … Review treatment & marketing records to assess prescription compliance. 45

46. Antibiotic Residue Avoidance Strategy • Identify all animals treated. • Record all treatments: • Date; animal’ ID; dose given; route of administration; the person who administered the treatment; withdrawal time (WD). • Strictly follow label directions for product use. • Use newer technology antibiotics when possible. • Select antibiotics with short WD when the choice is equivalent. • Never give more than 10 cc per IM injection site. • Avoid Extra Label Drug Use (ELDU) of antibiotics. • Avoid using multiple antibiotics at the same time. • Don’t mix antibiotics in the same syringe. • Check ALL medication/treatment records before marketing. 46

47. What can be done to protect our producers … & ourselves? • Use residue screening tests such as the urine adapted PremiTest or PHAST before “high-residue-risk” cattle are sold … • Will the test work “pre-harvest”? • Yes … BUT it is a microbial inhibition test and must use with knowledge of the sensitivity & the MRL • If the urine doesn’t inhibit the test … it is not likely tissue juices from the kidney will inhibit the test … a couple of potential exceptions … Gen & Neo PremiTest (DSM Corp), PHAST (Pre-Harvest Antibiotic Screening Test) 47

48. Testing Urine Isn’t Tough …(Pre-Harvest Antibiotic Screening Test) 48

49. PHAST (B. meg. FAST used on urine) “This little cow stays home” “This little cow gets to go to Market” 49

50. B. stearothermophilus DSM PremiTest, Charm KIS, 147⁰F (64 ⁰C) for 3 hrs