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Great Plains Veterinary Educational Center Breakpoint Clinical Considerations Dee Griffin

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1 Great Plains Veterinary Educational Center Breakpoint Clinical Considerations Dee Griffin

2 Great Plains Veterinary Educational Center An antibiotic breakpoint is a maximum MIC threshold for predicting successful antibiotic therapy … During the antibiotic dosing interval, organisms with an MIC at or below this threshold are expected to be inhibited as a minimum expectation or, better still, to be killed. This applies only to the immunocompetent patient whose host defenses will then provide the necessary antibacterial activity to resolve the infection.

3 Great Plains Veterinary Educational Center RESPIRATORY DISEASE This is where we start …

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5 Cattle are Prey Animals It’s in their genetic heritage not to look sick Finding sick cattle early … is not in our genetic heritage

6 Great Plains Veterinary Educational Center Seek & Treat … Less Than Perfect

7 Great Plains Veterinary Educational Center ADG Pulled vs Not-Pulled

8 Great Plains Veterinary Educational Center Dealing With Disease Find Sick Cattle Early Appetite & Depression

9 Great Plains Veterinary Educational Center Respiratory Disease Cost money … Cost performance …

10 Great Plains Veterinary Educational Center Offal Data Recorder Normal Lung Minor Purple Major Purple Minor Adhere Major Adhere Missing Lung Green Eosin Contam. Condemn Normal Heart Contam. Condemn Epi-Para Carditis Railed Out Other. NO Pregnancy RAILED OUT Normal Intestines Contam. Condemn Peritonitis Adhere Ulcer Ruptured Other. Normal Kidney Sm White Spots Large Spots Rough Surface Other. Normal Liver Minor Abscess Major Abscess Flukes Liver Telang Liver Para Scars Contam. Condemn Other. Trolley IDAnimal ID SubmitEDITCancel YES Active LN Condemned Contam. Condemn

11 Great Plains Veterinary Educational Center Lungs Lungs … MOST will NOT be associated with condemnation Minor Adhesions Look Like … Spider Web Strands

12 Great Plains Veterinary Educational Center Lungs Lungs … MOST will NOT be associated with condemnation Note the Skirt is adhered to the lung.

13 Great Plains Veterinary Educational Center Lungs Lungs … MOST will NOT be associated with condemnation Note the Skirt is adhered to the lung. Note: Lung was condemned … this is good evidence there was an active infection (could also record as “Active LN”) Note: Most of both sides are missing. Note: Lung was condemned … this is good evidence there was an active infection (could also record as “Active LN”) Note: Part of Lung is still in the chest

14 Great Plains Veterinary Educational Center Lungs Lungs … MOST will NOT be associated with condemnation Note: Lung was condemned … this is good evidence there was an active infection (could also record as “Active LN”) Note: Young Lesions are Bloody

15 Great Plains Veterinary Educational Center Stripped Plura

16 Great Plains Veterinary Educational Center Lung Lesions

17 Great Plains Veterinary Educational Center Lung Lesions Cost Performance Buhman, NU-GPVEC 2001

18 Great Plains Veterinary Educational Center Data from Different Sources DescriptionADGMarblingRef No Rx vs 2 RX- 0.37~ Missouri No Rx vs 2 RX- 0.45~ - 100Colorado No Rx vs 2 RX JAVMA Health vs Sick / -35Texas Health vs Sick Smith Lung Lesions Bryant Lung Lesions Bryant Lung Active Bryant Lung All/Severe-.06/ / - 78GPVEC

19 Great Plains Veterinary Educational Center Dealing with Respiratory Disease

20 Great Plains Veterinary Educational Center Select appropriate high quality products Most commonly, BRD has a head start in high- stressed young commingled cattle.

21 Great Plains Veterinary Educational Center Durable Cure & DART The goal: – 1) A first-time treated animal is more likely to become a high-performing, profitable animal ; – 2) That animal stays with its group mates and does not suffer a disease relapse. D.A.R.T. – An acronym for four areas that MUST be thoroughly assessed and monitored, – especially high stress or high risk of disease. – Depression, Appetite, Respiratory index & Temperature.

22 Great Plains Veterinary Educational Center Durable Cure & DART Depression is rated on four levels: –Normal, mild, moderate and severe. –A normal animal is alert and moves with its group mates. –Mild depression may include signs like droopy ears or head, but the animal is easily stimulated into normal behavior. –Moderate depression means an animal appears listless and acts sore. It responds to stimulation but does not behave like its group mates. –An animal with severe depression is too weak to walk and looks close to dying.

23 Great Plains Veterinary Educational Center Durable Cure & DART Appetite: –One of the first signs of many systemic diseases, such as respiratory, intestinal or severe reproductive infections can be loss of appetite. –Animals are going off feed when they fail to show interest in feed. –Watch your animal’s response to feed deliver. –If they do not appear interested something may be wrong. –Try to catch animals before they have been off feed long enough to lack fill and appear - gaunt.

24 Great Plains Veterinary Educational Center Durable Cure & DART Respiratory Index: –An additional sign of many systemic diseases is an irregular breathing pattern. –This is especially true if the animal is suffering from respiratory disease. –Its respiratory rate can be accelerated, its effort to take breaths can be exaggerated, and the depth of its breaths can be noticeably different. –Essentially, an animal's respiratory index is abnormal when its rate, depth and effort differ from those of its normal group mates.

25 Great Plains Veterinary Educational Center Durable Cure & DART Temperature: –The normal temperature of a healthy cow or calf is approximately 102.5° F. –The temperature can is influence not only by disease, but by the animal’s environment, housing, and temperament. –Remember if appropriate; adjust your definition of normal temperature to account for these factors.

26 Great Plains Veterinary Educational Center How Sick Cattle Eat Pull any new calf that is slow to come to the bunk Look for sick cattle shortly after putting out feed.

27 Great Plains Veterinary Educational Center Sick: Intake vs. Temp

28 Great Plains Veterinary Educational Center Subclinical Acidosis

29 Great Plains Veterinary Educational Center Understand the Problem … Diagnoses & Cause ?

30 Great Plains Veterinary Educational Center Vets have a symbiotic relationship with Nuts Vets … Work with MEDS Nuts … Work with RATS Very important to understand the relationship between cattle health and nutrition !!!

31 Great Plains Veterinary Educational Center Finding Sick Cattle Early … may be an impossible job

32 Great Plains Veterinary Educational Center Prevention … is key Treatment salvages only part of the loss Immune preparation Treatment timing

33 Great Plains Veterinary Educational Center 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

34 Great Plains Veterinary Educational Center 7 Antibiotic Use Myths … Dr. Mike Apley 1.Two antibiotics work twice as well as one 2.You must give an IV to get a quick response 3.If they have not responded to the first, switch to another 4.Aggressive is good. If they don’t look better in 24 hours, add the next drug in the rotation to the first treatment 5.The hotter they are, the sicker they are, so make drug choices based upon rectal temperature 6.Adding supportive drugs will improve response 7.Vaccination at time of treatment improves response

35 Great Plains Veterinary Educational Center What happened? … a look at the Sequence Example: Respiratory System

36 Great Plains Veterinary Educational Center 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.

37 Great Plains Veterinary Educational Center 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

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42 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 …

43 Great Plains Veterinary Educational Center 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

44 Great Plains Veterinary Educational Center Antimicrobial groups approved for cattle: Antibiotic ClassAntibiotic Within Class Resistance Mechanism Lipid Solubility ~ Protein Binding % AminocyclitolsSpectinomycin PS Low AminoglycosidesGentamicin, Neomycin PS Low 20-25% Beta-lactamsPenicillin G, Ampicillin, Ceftiofur CW Low P&A 20, Cef 80+ Chloramphenicol derivatives Florfenicol PS High 60 FluoroquinolonesEnrofloxacin, Danofloxacin GR High Low LincosamidesLincomycin PS High MacrolidesErythromycin, Tilmicosin, Tylosin PS High SulfonamidesSulfa - dimethoxine, methazine, chlorpyridazine MP Low SM 70, SDM TetracyclinesOxytetracycline, Chlortetracycline PS Intermediate OTC 20-25, CTC 65 CW crippling production of the bacterial cell wall that protects the cell from the external environment PS interfering with protein synthesis by binding to the machinery that builds proteins, amino acid by amino acid MP wreaking havoc with metabolic processes, such as the synthesis of folic acid, that bacteria need to thrive GR blocking genetic replication by interfering with synthesis of DNA and RNA

45 Great Plains Veterinary Educational Center PK / PD Relationships

46 Great Plains Veterinary Educational Center Antibiotic Movement

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48 What Does This Mean? What Value is This?

49 Great Plains Veterinary Educational Center the different classes of antibiotics … & … what makes them different

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51 Pen G Dose Curves

52 Great Plains Veterinary Educational Center Ceftiofur Dose Curves

53 Great Plains Veterinary Educational Center Ceftiofur Sensitivity (VADS) P. multocida (498) MICIncidenceCumulative % 10.40%99.60% 20.20%99.80% 40.00%99.80% 80.00%99.80% %100.00% M. haemolytica (481) MICIncidenceCumulative % 10.21%99.58% 20.00%99.58% 40.21%99.79% 80.00%99.79% %100.00%

54 Great Plains Veterinary Educational Center Ceftiofur Sensitivity (VADS) H. somni (208) MICIncidenceCumulative % 11.44%100.00% 20.00%100.00% 40.00%100.00% 80.00%100.00% %100.00% S. typhimurium (66) MICIncidenceCumulative % %96.97% 21.52%98.48% 40.00%98.48% 80.00%98.48% %100.00%

55 Great Plains Veterinary Educational Center Oxytet Dose Curves

56 Great Plains Veterinary Educational Center Oxytet Sensitivities (VADS) P. multocida (498) MICIncidenceCumulative % %45.98% %56.43% 23.01%59.44% 41.41%60.84% 82.81%63.65% %100.00% M. haemolytica (481) MICIncidenceCumulative % %44.91% 12.49%47.40% 20.83%48.23% 42.70%50.94% %65.49% %100.00%

57 Great Plains Veterinary Educational Center Oxytet Sensitivities (VADS) H. somni (208) MICIncidenceCumulative % %59.62% 13.37%62.98% 20.00%62.98% 42.88%65.87% %79.33% %100.00% S. typhimurium (66) MICIncidenceCumulative % % 10.00%1.52% %15.15% 43.03%18.18% 80.00%18.18% %100.00%

58 Great Plains Veterinary Educational Center Macrolide Dose Curves

59 Great Plains Veterinary Educational Center 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 ???

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62 how the other things we give sick cattle can influence an antibiotic's effectiveness The stress caused by some products does more damage than their benefit –Injection site irritation ??? –Restraint for IV injection … IV-ing ability Product interferes with antibiotic –Sulfa’s and folic acid (a “B” vitamin)

63 Great Plains Veterinary Educational Center “May Help … What It Don’t Hurt”

64 Great Plains Veterinary Educational Center Injection Sites … New Concerns

65 Great Plains Veterinary Educational Center Knots aren’t Bad

66 Great Plains Veterinary Educational Center PTI (Post Treatment Interval) Economics

67 Great Plains Veterinary Educational Center PTI (Post Treatment Interval) Economics

68 Great Plains Veterinary Educational Center PK & PD Compared

69 Great Plains Veterinary Educational Center Dose Price Compared

70 Great Plains Veterinary Educational Center PTI Example … Draxxin Percent treatment Success, re-treatments & BRD associated chronic and mortalities. Re - TreatmentsBRD Success1st2nd3rdCM 7 day day day allocated in all treatment intervals … Non-BRD removals: 7 day (5), 10 (2), 14 (3) Average daily gain mean and range in pounds LS MeanMedianRange 7 day (-0.18, 4.14) 10 day (0.64, 4.46) 14 day (-0.79, 4.14)

71 Great Plains Veterinary Educational Center PTI Example … The deal is it changes the flow Cumulative 1st Re-Treatments

72 Great Plains Veterinary Educational Center 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 CAUTIONCAUTION – Generics … & AVOID Bathtub mixes Neomycin & Gentamicin … violate BQA & reason

73 Great Plains Veterinary Educational Center how to know when to switch 1 st … 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

74 Great Plains Veterinary Educational Center 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 !

75 Great Plains Veterinary Educational Center why an antibiotic may seem to work on some sets of cattle and not others BIGGEST FACTOR … TIMING!!! –How much of a head start ??? Animal’s ability to help fight back Differences in bugs … Diagnosis ??? … When to Quit and Let Go

76 Great Plains Veterinary Educational Center 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? … Quit when you win… temp down, gaining weight for 48 hours QUITIf 1 is over 21 days & 2 is over 7 days … QUIT QUITIf 2 is greater than 10 … QUIT

77 Great Plains Veterinary Educational Center when to quit when to quit letting go

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80 Food Animal Therapeutic Management is Not Complete Until The Residue Potential Is Considered & Managed

81 Great Plains Veterinary Educational Center A Producers Guide for Judicious Use of Antimicrobials in Cattle (As Adopted by the NCBA.) 1.Prevent Problems: Emphasize appropriate husbandry and hygiene, routine health examinations, and vaccinations. 2.Select and Use Antibiotics Carefully: Consult with your veterinarian on the selection and use of antibiotics. Have a valid reason to use an antibiotic. Therapeutic alternatives should be considered prior to using antimicrobial therapy. 3.Avoid Using Antibiotics Important In Human Medicine As First Line Therapy: Avoid using as the first antibiotic those medications that are important to treating strategic human or animal infections. 4.Use the Laboratory to Help You Select Antibiotics: Cultures and susceptibility test results should be used to aid in the selection of antimicrobials, whenever possible. 5.Combination Antibiotic Therapy Is Discouraged Unless There Is Clear Evidence The Specific Practice Is Beneficial: Select and dose an antibiotic to affect a cure. 6.Avoid Inappropriate Antibiotic Use: Confine therapeutic antimicrobial use to proven clinical indications, avoiding inappropriate uses such as for viral infections without bacterial complication. 7.Treatment Programs Should Reflect Best Use Principles: Regimens for therapeutic antimicrobial use should be optimized using current pharmacological information and principles. 8.Treat the Fewest Number of Animals Possible: Limit antibiotic use to sick or at risk animals. 9.Treat for the Recommended Time Period: To minimize the potential for bacteria to become resistant to antimicrobials. 10.Avoid Environmental Contamination with Antibiotics: Steps should be taken to minimize antimicrobials reaching the environment through spillage, contaminated ground run off or aerosolization. 11.Keep Records of Antibiotic Use: Accurate records of treatment and outcome should be used to evaluate therapeutic regimens and always follow proper withdrawal times. 12.Follow Label Directions: Follow label instructions and never use antibiotics other than as labeled without a valid veterinary prescription. 13.Extralabel Antibiotic Use Must follow FDA Regulations: Prescriptions, including extra label use of medications must meet the Animal Medicinal Drug Use Clarification Act (AMDUCA) amendments to the Food, Drug, and Cosmetic Act and its regulations. This includes having a valid Veterinary-Client-Relationship. 14.Subtherapeutic Antibiotic Use Is Discouraged: Antibiotic use should be limited to prevent or control disease.

82 Great Plains Veterinary Educational Center Antibiotic MRL (Tolerance)

83 Great Plains Veterinary Educational Center Test to Reg. Differences Note: From the USDA-FSIS Domestic Residue Plan “Blue Book” page 10. “beta-lactams (quantitated as penicillin- G; penicillins and cephalosporins are not differentiated within this category). Therefore ceftiofur will be false positive and not differentiated from penicillin. (last publication released 2005) Book_Vet_Drugs_%20Dom_Tables_1_thr u_6B.pdf

84 Great Plains Veterinary Educational Center Ben. Pen. Residue Potential

85 Great Plains Veterinary Educational Center What can be done to protect our producers … & ourselves? Use FAST (PHAST) before “high- residue-risk” cattle are sold …Use FAST (PHAST) before “high- residue-risk” cattle are sold … Will the test work “pre-harvest”? –Based on everything I know and have done in my lab … it will work as well as LAST 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 …

86 Great Plains Veterinary Educational Center Testing Urine Isn’t Tough …

87 Great Plains Veterinary Educational Center Antibiotic Residue Avoidance Strategy 1.Identify all animals treated. 2.Record all treatments: Date; animal’ ID; dose given; route of administration; the person who administered the treatment; withdrawal time (WD). 3.Strictly follow label directions for product use. 4.Use newer technology antibiotics when possible. a.Reduce unwanted depot effect. Select low volume products when available. b.Select generic medications and vaccines with EXTREME CAUTION. c.Avoid inferior products. They may cause performance loss or damage quality. 5.Select with short WD when antibiotic choice is equivalent. 6.Never give more than 10 cc per IM injection site. 7.Avoid Extra Label Drug Use (ELDU) of antibiotics. a.Use label dose and route of administration. 8.Avoid using multiple antibiotics at the same time. 9.Don’t mix antibiotics in the same syringe, especially if given IM or Sub-Q.

88 Great Plains Veterinary Educational Center Antibiotic Residue Avoidance Strategy 10.Check ALL medication/treatment records before marketing: a.Don’t market cattle with less than 60 WD without examining the treatment history. b.Extend the WD time if the route or location of administration is altered. 1.Example; the WD for ear route of administration ceftiofur will be over 120 days if given SQ in the neck. 2.Example; tissue irritation will cause the WD for Banamine to be over 30 days if given IM or Sub-Q instead of IV. c.Extend the withdrawal time for multiple medications given by summing their label recommended WD. 1.Example; if the 1st medication has a 10 day WD and the 2nd medication has a 28 day WD, assign a 38 day. WD. 2.Example; if 1st medication has a 10 day WD and is repeated in three days, assign a 20 day WD.

89 Great Plains Veterinary Educational Center Antibiotic Residue Avoidance Strategy d.Extend the WD for all penicillin given at doses which exceed the label dose 1.Example; the WD for Procaine Pen G given at 3 CC per CWT IM or Sub-Q is over 30 days 2.Example; the WD for Procaine Pen G given at 4 CC per CWT IM or Sub-Q is over 30 days 3.Example; the WD for Long Acting Pen G given at 3 CC per CWT IM or Sub-Q is over 120 days 4.Example; the WD for Long Acting Pen G given at 4 CC per CWT IM or Sub-Q is over 180 days 1.Testing urine test may not detect injection site residues and will test positive by the USDA-FSIS. e.Never inject gentamicin or neomycin. The estimated WD is over 24 months 1.Testing urine test may not detect a kidney that will test positive by the USDA-FSIS.

90 Great Plains Veterinary Educational Center Antibiotic Residue Avoidance Strategy f.USDA-FSIS. Don’t market cattle with suspected liver or kidney damage without examining the treatment history. g.Don’t market cattle with antibiotic injection site knots without examining the treatment history. h.Screen the urine for antibiotics of all cattle identified in steps a- d above. It is best to use broad spectrum microbial inhibition test such as the Pre-Harvest Antibiotic Screening Test (PHAST), a microbial growth inhibition test which uses B. megaterium as the test organism. Test sensitivity relative to FDA-CVM violative residue tolerances (Maximum Residue Limit or MRL)

91 Great Plains Veterinary Educational Center Save a Cow … Eat a Vegetarian Good Luck To You

92 Great Plains Veterinary Educational Center Thanks for having me … & we would love to have you come see us…...where agriculture & all it’s people make a difference

93 Great Plains Veterinary Educational Center The Ear Is A Busy Place

94 Great Plains Veterinary Educational Center Comparison of two drugs for treatment of a gram-negative bacterial infection Drug A- fluoroquinolone; –Cmax: 6 mg/L … T1/2: 4 hr … 24 hr AUC: 70 mg-hr/L –MIC90: 2 mg/L Drug B: cephalosporin; –Cmax: 32 mg/L … T1/2: 2 hr … 24 hr AUC: 27 mg-hr/L –MIC90: 4 mg/L Which is the “better” drug? –Fluoroquinolone: 24 hr AUC:MIC90 = 70/2 = 35 –Cephalosporin: %T>MIC90 = 6 hr/8 hr interval = 75% Therefore, in this case … –cephalosporin is superior to the quinolone

95 Great Plains Veterinary Educational Center Comparing Antimicrobial Activity In Vivo Comparing MICs – Assumes similar pharmacokinetics – Assumes similar pharmacodynamics (apples vs. oranges) Comparing MICs vs. “breakpoints” – Crude estimates – Assumes higher breakpoint/MIC ratio is better Comparing PK/PD measures

96 Great Plains Veterinary Educational Center Establishing MIC Breakpoints Breakpoint established arbitrarily => Drug used clinically => Breakpoint revised Appropriate PK/PD identified for class => Magnitude of PK/PD for efficacy established => Antibiotic PK profile measured => Breakpoint revised

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100 Building Resistance

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102 Antimicrobial Model Successful treatment of infection involves the interactions of host, drug and bacteria HostDrug Bacteria s Pharmacokinetics Tissue penetration Susceptibility of pathogens PK/PD relationship PAE Killing rate Other metrics Immune system ? ? ? ?    The factors not being considered may represent potential limitations.

103 Great Plains Veterinary Educational Center Appropriate Pharmacokinetic/Pharmacodynamic Measures to Assess Antimicrobial Activity In Vivo Drug Conc -Cidal Activity PAE PK/PD Measures Beta-lactamFixedMinimalT>MIC MacrolideFixedSomeT>MIC AzalideFixedLongerAUC:MIC AminoglycosideLinearSomeAUC:MIC

104 Great Plains Veterinary Educational Center Please know, We take our responsibility to use antibiotics properly very seriously …


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