What Those of Us Who Are Not Pharmacologist Need To Know About Selection Use of Antibiotics

1. What Those of Us Who Are Not Pharmacologist Need To Know About Selection & Use of Antibiotics The objective will be to help better understand: 1) how viruses and bacteria cause different diseases 2) how the antibiotics they use work 3) antibiotics role in treating diseases caused by different bugs 4) antibiotic classes � and what makes them different 5) why an antibiotic seems to work on some cattle & not others 6) how the other things we give sick cattle can influence an antibiotic's effectiveness 7) how to select a proper antibiotic for different diseases 8) how to know when to switch 9) which antibiotic would make a better choice when you need to switch if an animal doesn't respond 10) when to quit 1

2. Parts of the Puzzle

3. how viruses & bacteria cause different diseases Antibiotics do not work on viruses because viruses are not alive A virus injects its DNA into a living cell and has that cell reproduce more of the viral DNA. With a virus there is nothing to "kill," so antibiotics don't work on it. Viruses take over living cells � make the cell do what the virus demands � then leaves � cell is weaken or dead

5. how viruses & bacteria cause different diseases Bacteria are single-cell organisms Bacteria produce chemicals that damage or disable cells body cells Different types of antibiotics affects different bacteria in different ways

6. the role of antibiotics in treating diseases caused by different bugs � focus on respiratory disease Shipping fever / BRD � set up by commingling, lack of immune protection stress 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

9. 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.

10. 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

13. 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 �

14. 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

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16. the different classes of antibiotics and what makes them different

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20. PK / PD Relationships

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22. Antibiotic Movement

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26. why an antibiotic may seem to work on some sets of cattle and not others Source, Source, & Source BIGGEST FACTOR � TIMING!!! How much of a head start ??? Animal�s ability to help fight back Differences in bugs � Diagnosis ???

27. Prevention � is key Treatment salvages only part of the loss Immune preparation Treatment timing

28. Dealing With Disease Don�t let your thermometer do your thinking! 28

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30. Finding Sick Cattle � Can you spell � DART => Depression => Appetite => Respiration => Temperature

31. Finding Sick Cattle � Number one rule: ...Have plenty of timeearly every morning........If the temperature is going to be over 70-80 F that day ...... Be finished by 10AM RELOOK AT CATTLE OFTEN

32. how to select a proper antibiotic for different diseases � will focus on BRD Pneumonia � Ab penetration not as much of a problem early as late Bugs that live in cells � need Ab that crosses cell walls Animal�s that are over whelmed & can�t help the drug by fighting back � cidal Ab may be better than static Ab Can�t defend the use of Pen G (especially LA Pen) & Sulfa in BRD Rx programs CAUTION � Generics �& AVOID Bathtub mixes Neomycin & Gentamicin � violate BQA & reason

33. how to know when to switch 1st � and very important � assess the �stress� effect of the Ab gut fill, soreness, tissue temp, etc don�t switch because of stress effect Monitor animal NOT temp!!! Don�t let the thermometer do your thinking Use temp to confirm your visual assessment Give the Ab 48 hours � @ MIC 90

34. which antibiotic would make a better choice when you need to switch � poor response Re-check the diagnosis � & evaluate the treatment extras being used Use previous lab work � animals that die may be the most valuable If the infection is winning � get meaner Cidal Ab KILL bugs � good selection Ab that penetrate � good selection Ab that minimizes stress effect � may be good Have faith in the treatment plan � stick to it !

35. Letting go Giving up on a sick animal that has failed to recover is one of the toughest things we ask our treatment crew to do. Medications given to sick cattle that repeatedly fail to respond are extremely expensive. Recognizing when it is time to stop therapy is tough, but simple rules for when to stop must be developed and enforced.

36. Letting go Total cost of therapy may be a good guideline, but should be included with decisions based on the number of therapy days. Management should evaluate continue therapy on all sick cattle that fail to respond with in seven days.

37. when to quit Consider two things � 1) How long ago did the �stress� start ??? Auction market � days received + 3 days 2) How long have you been treating animal? If 1 is over 21days & 2 is over 7days � QUIT If 2 is greater than 10 � QUIT 37

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40. Responsible Use Considers RESIDUE AVOIDANCE 40

41. 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.� 41

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43. 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 43

44. 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. 44

45. 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 45

46. 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 46

47. 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. 47

48. Total Cattle Marketed 48

49. Chemical Defects � Residues 1982 � just under 2% of all beef cattle 2007 �Random samples: Zero antibiotics, 0.3% avermectin & sulfa 49

50. Chemical Defects � ResiduesOTC vs Vet Rx 50

51. 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.) 51

52. Flunixin Residues:USDA-FSIS Oct 2009 Currently investigating 146 Flunixin Residues Violations 52\

53. Sulfa Residues: 53

54. Chemical Defects � Residues 1982 � just under 2% of all cattle 2007 �Random samples: Zero antibiotics, 0.3% avermectin & sulfa 54

55. 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? 55

56. June 2007 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) 56

57. �How often do you look at your clients written treatment records?� June 2007 57

58. �How often do you think producers will not comply with instructions & will cause a violative residue?� June 2007 58

59. Ceftiofur Residues � �The Most Probable Cause� Ceftiofur Na� the �zero� withdrawal antibiotic (CM = 14 ug/ml, T� =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 59

60. RESIDUE AVOIDANCE � Carefully evaluate your ELDU & the extended withdrawals you assign. � Review treatment & marketing records to assess prescription compliance. 60

61. 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. 61

62. 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 62

63. Testing Urine Isn�t Tough �(Pre-Harvest Antibiotic Screening Test)

64. PHAST (B. meg. FAST used on urine) 64

65. B. stearothermophilus DSM PremiTest, Charm KIS, 147�F (64 �C) for 3 hrs 65

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67. What is the most important position our profession & industry can have? DON�T SEND CATTLE TO MARKET WITH A RESIDUE! 67

68. 68 In the world of food Consumers Purchase BUY WHAT THEY TRUST