2An 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.
10Offal Data Recorder Normal NO Submit EDIT Cancel YES Lung Minor Purple Major PurpleMinor AdhereMajor AdhereMissing LungGreen EosinContam. CondemnHeartEpi-Para CarditisRailed OutOtherNOPregnancyRAILED OUTIntestinesPeritonitis AdhereUlcer RupturedKidneySm White SpotsLarge SpotsRough SurfaceLiverMinor AbscessMajor AbscessFlukes LiverTelang LiverPara ScarsTrolley IDAnimal IDSubmitEDITCancelYESActive LN CondemnedOffal Data RecorderContam. CondemnOffal Inspection – Viscera Defect RecorderSix sets of observations will be takenLungs, Liver, Heart, Intestines, Kidneys, and PregnancyEnter the observation for each of these organThe EDIT button allows you to change entries.The CANCEL button allows you to cancel an entryThe SUBMIT button ends the data entry and brings up the ID of the next animal.
11Lungs Minor Adhesions Look Like … Spider Web Strands Lungs … MOST will NOT be associated with condemnationLungs … MOST will NOT be associated with condemnationMajor Purple: Lung Areas will be depressed purple areas as large or larger than the small lung lobes close to the trachea.Minor Adhere: These are spider web strands or tags of adhesions on the surface of the lungMinor Adhesions Look Like … Spider Web Strands
12Lungs Lungs … MOST will NOT be associated with condemnation Major Adhere: These are thick tags of adhesions on the between the lung lobes or on the surface of the lungMissing Lung: Part of the lung is missing … almost always the parts close to the trachea. If the missing lung part is associated with an active infection the inspector will condemn the lung.Note the Skirt is adhered to the lung.
13Lungs 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 the Skirt is adhered to the lung.Note: Most of both sides are missing.Lungs … MOST will NOT be associated with condemnationMissing Lung: Part of the lung is missing … almost always the parts close to the trachea. If the missing lung part is associated with an active infection the inspector will condemn the lung.Generally, the missing part of the lung will be found in the animals chest cavity. Which will cause the pleura to be stripped out.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
14Lungs 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”)Lungs … MOST will NOT be associated with condemnationActive LN Condemn: Are lungs with active infections as judged by the lymph nodes (LN) being swollen and inflamed.Green Eosin: Are greenish blood spots in the lung. These are usually the size of a dime or nickel. The larger the spot the bloodier it will appear. As the the lesion ages it becomes smaller and more greenish.Note: Young Lesions are Bloody
20Select appropriate high quality products Most commonly, BRD has a head start in high-stressed young commingled cattle.
21Durable Cure & DART The goal: D.A.R.T. 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.
22Durable 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.
23Durable 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.
24Durable 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.
25Durable 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.
26How Sick Cattle Eat Pull any new calf that is slow to come to the bunk Look for sick cattle shortly after putting out feed.
30Vets have a symbiotic relationship with Nuts Work withMEDSNuts …Work withRATSVery important to understand the relationship between cattle health and nutrition !!!
31Finding Sick Cattle Early … may be an impossible job
32Prevention … is key Treatment salvages only part of the loss Immune preparationTreatment timing
33What You Need to Know &Think About When Selecting Antibiotics The objective will be to help folks better understand:1) how antibiotics work … clinically2) antibiotic classes … & what makes them different3) how to think through developing treatment protocols4) understand dose management & resistance development5) how to select a proper antibiotic for different diseases6) how the other things given sick cattle can influence an antibiotic's effectiveness7) how to know when to switch8) which antibiotic would make a better choice when a switch is need if an animal doesn't respond9) when to quit10) potential residue considerations & management
347 Antibiotic Use Myths … Dr. Mike Apley Two antibiotics work twice as well as oneYou must give an IV to get a quick responseIf they have not responded to the first, switch to anotherAggressive is good. If they don’t look better in 24 hours, add the next drug in the rotation to the first treatmentThe hotter they are, the sicker they are, so make drug choices based upon rectal temperatureAdding supportive drugs will improve responseVaccination at time of treatment improves response
35What happened? … a look at the Sequence Example: Respiratory System
36Disease 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.
37Disease 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
42how the antibiotics work Antibiotic – mold, 1928Protect molds from bacteriaNo effect on viruses or normal body cellsTwo types -static (slows) & cidal (kills)Four mechanismsCripples cell wallInterferes with protein synthesisConfuses metabolic processesBlocks DNA / RNA synthesisDifferent bacteria … require different mechanisms to stop them …
44Antimicrobial groups approved for cattle: Antibiotic ClassAntibiotic Within ClassResistanceMechanismLipid Solubility~ ProteinBinding %AminocyclitolsSpectinomycinPSLowAminoglycosidesGentamicin, Neomycin20-25%Beta-lactamsPenicillin G, Ampicillin, CeftiofurCWP&A 20, Cef 80+Chloramphenicol derivativesFlorfenicolHigh60FluoroquinolonesEnrofloxacin, DanofloxacinGRLincosamidesLincomycin55-75MacrolidesErythromycin, Tilmicosin, Tylosin70-80SulfonamidesSulfa - dimethoxine, methazine, chlorpyridazineMPSM 70, SDM 80-85TetracyclinesOxytetracycline, ChlortetracyclineIntermediateOTC 20-25, CTC 65crippling production of the bacterial cell wall that protects the cell from the external environmentinterfering with protein synthesis by binding to the machinery that builds proteins, amino acid by amino acidwreaking havoc with metabolic processes, such as the synthesis of folic acid, that bacteria need to thriveblocking genetic replication by interfering with synthesis of DNA and RNA
59BIGGEST FACTOR … TIMING!!! Animal’s ability to help fight back why an antibiotic may seem to work on some sets of cattle and not othersSource, Source, & SourceBIGGEST FACTOR … TIMING!!!How much of a head start ???Animal’s ability to help fight backDifferences in bugs …Diagnosis ???
62The stress caused by some products does more damage than their benefit how the other things we give sick cattle can influence an antibiotic's effectivenessThe stress caused by some products does more damage than their benefitInjection site irritation ???Restraint for IV injection … IV-ing abilityProduct interferes with antibioticSulfa’s and folic acid (a “B” vitamin)
70PTI Example … Draxxin Percent treatment Success, re-treatments & BRD associated chronic and mortalities.Re - TreatmentsBRDSuccess1st2nd3rdCM7 day220.127.116.11.80.410 day85.312.41.614 day88.81.2253 allocated in all treatment intervals … Non-BRD removals: 7 day (5), 10 (2), 14 (3)Average daily gain mean and range in poundsLS MeanMedianRange7 day2.72.72(-0.18 , 4.14)10 day2.73(0.64 , 4.46)14 day2.552.57(-0.79 , 4.14)7Animal 0320 was euthanatized 30 Oct 2005; necropsy indicated brain edema and hyperemia.Animal 0066 died 16 Nov 2005; necropsy indicated cardiac failure due to chronic hardware.Animal 1010 died 06 Dec 2005; necropsy indicated polio.Animal 1104 was treated (Nuflor) 14 Dec 2005 for lameness and subsequently euthanatized 16 Dec 2005.Animal 0012 removed from analysis because of protocol deviation10Animal 0457 died 8 Nov 2005; necropsy indicated petechial hemorrhages throughout abdomen.Animal 0527 removed from analysis because of protocol deviation14Animal 0035 was treated (Nuflor) 23 Nov 2005 for foot rot. Animal 0046 was treated (Nuflor) 23 Nov 2005 for foot rot. Animal 0474 was treated (tetracycline, dexamethasone) 14 Dec 2005 for polio.
71PTI Example … The deal is it changes the flow Cumulative 1st Re-Treatments7Animal 0320 was euthanatized 30 Oct 2005; necropsy indicated brain edema and hyperemia.Animal 0066 died 16 Nov 2005; necropsy indicated cardiac failure due to chronic hardware.Animal 1010 died 06 Dec 2005; necropsy indicated polio.Animal 1104 was treated (Nuflor) 14 Dec 2005 for lameness and subsequently euthanatized 16 Dec 2005.Animal 0012 removed from analysis because of protocol deviation10Animal 0457 died 8 Nov 2005; necropsy indicated petechial hemorrhages throughout abdomen.Animal 0527 removed from analysis because of protocol deviation14Animal 0035 was treated (Nuflor) 23 Nov 2005 for foot rot. Animal 0046 was treated (Nuflor) 23 Nov 2005 for foot rot. Animal 0474 was treated (tetracycline, dexamethasone) 14 Dec 2005 for polio.
72how to select a proper antibiotic for different diseases … will focus on BRD Pneumonia … Ab penetration not as much of a problem early as lateBugs that live in cells … need Ab that crosses cell wallsAnimal’s that are over whelmed & can’t help the drug by fighting back …cidal Ab may be better than static AbCan’t defend the use of Pen G (especially LA Pen) & Sulfa in BRD Rx programsCAUTION – Generics … & AVOID Bathtub mixesNeomycin & Gentamicin … violate BQA & reason
73how to know when to switch 1st … and very important … assess the “stress” effect of the Abgut fill, soreness, tissue temp, etcdon’t switch because of stress effectMonitor animal NOT temp!!!Don’t let the thermometer do your thinkingUse temp to confirm your visual assessmentGive the Ab 48 hours MIC 90
74Re-check the diagnosis … Use previous lab work … which antibiotic would make a better choice when you need to switch … poor responseRe-check the diagnosis …& evaluate the treatment extras being usedUse previous lab work …animals that die may be the most valuableIf the infection is winning … get meanerCidal Ab KILL bugs … good selectionAb that penetrate … good selectionAb that minimizes stress effect … may be goodHave faith in the treatment plan … stick to it !
75… When to Quit and Let Go BIGGEST FACTOR … TIMING!!! why an antibiotic may seem to work on some sets of cattle and not othersBIGGEST FACTOR … TIMING!!!How much of a head start ???Animal’s ability to help fight backDifferences in bugs …Diagnosis ???… When to Quit and Let Go
76when to quit Consider two things … 1) How long ago did the “stress” start ???Auction market … days received + 3 days2) How long have you been treating animal?… Quit when you win… temp down, gaining weight for 48 hoursIf 1 is over 21days & 2 is over 7days … QUITIf 2 is greater than 10 … QUIT
80Food Animal Therapeutic Management is Not Complete Until The Residue Potential Is Considered & Managed
81A Producers Guide for Judicious Use of Antimicrobials in Cattle (As Adopted by the NCBA.) Prevent Problems: Emphasize appropriate husbandry and hygiene, routine health examinations, and vaccinations.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.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.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.Combination Antibiotic Therapy Is Discouraged Unless There Is Clear Evidence The Specific Practice Is Beneficial: Select and dose an antibiotic to affect a cure.Avoid Inappropriate Antibiotic Use: Confine therapeutic antimicrobial use to proven clinical indications, avoiding inappropriate uses such as for viral infections without bacterial complication.Treatment Programs Should Reflect Best Use Principles: Regimens for therapeutic antimicrobial use should be optimized using current pharmacological information and principles.Treat the Fewest Number of Animals Possible: Limit antibiotic use to sick or at risk animals.Treat for the Recommended Time Period: To minimize the potential for bacteria to become resistant to antimicrobials.Avoid Environmental Contamination with Antibiotics: Steps should be taken to minimize antimicrobials reaching the environment through spillage, contaminated ground run off or aerosolization.Keep Records of Antibiotic Use: Accurate records of treatment and outcome should be used to evaluate therapeutic regimens and always follow proper withdrawal times.Follow Label Directions: Follow label instructions and never use antibiotics other than as labeled without a valid veterinary prescription.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.Subtherapeutic Antibiotic Use Is Discouraged: Antibiotic use should be limited to prevent or control disease.
83Test 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)
85What can be done to protect our producers … & ourselves? 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 LASTIf 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 …
87Antibiotic 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.Reduce unwanted depot effect. Select low volume products when available.Select generic medications and vaccines with EXTREME CAUTION.Avoid inferior products. They may cause performance loss or damage quality.Select with short WD when antibiotic choice is equivalent.Never give more than 10 cc per IM injection site.Avoid Extra Label Drug Use (ELDU) of antibiotics.Use label dose and route of administration.Avoid using multiple antibiotics at the same time.Don’t mix antibiotics in the same syringe, especially if given IM or Sub-Q.
88Antibiotic Residue Avoidance Strategy Check ALL medication/treatment records before marketing:Don’t market cattle with less than 60 WD without examining the treatment history.Extend the WD time if the route or location of administration is altered.Example; the WD for ear route of administration ceftiofur will be over 120 days if given SQ in the neck.Example; tissue irritation will cause the WD for Banamine to be over 30 days if given IM or Sub-Q instead of IV.Extend the withdrawal time for multiple medications given by summing their label recommended WD.Example; if the 1st medication has a 10 day WD and the 2nd medication has a 28 day WD, assign a 38 day. WD.Example; if 1st medication has a 10 day WD and is repeated in three days, assign a 20 day WD.
89Antibiotic Residue Avoidance Strategy Extend the WD for all penicillin given at doses which exceed the label doseExample; the WD for Procaine Pen G given at 3 CC per CWT IM or Sub-Q is over 30 daysExample; the WD for Procaine Pen G given at 4 CC per CWT IM or Sub-Q is over 30 daysExample; the WD for Long Acting Pen G given at 3 CC per CWT IM or Sub-Q is over 120 daysExample; the WD for Long Acting Pen G given at 4 CC per CWT IM or Sub-Q is over 180 daysTesting urine test may not detect injection site residues and will test positive by the USDA-FSIS.Never inject gentamicin or neomycin. The estimated WD is over 24 monthsTesting urine test may not detect a kidney that will test positive by the USDA-FSIS.
90Antibiotic Residue Avoidance Strategy USDA-FSIS. Don’t market cattle with suspected liver or kidney damage without examining the treatment history.Don’t market cattle with antibiotic injection site knots without examining the treatment history.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)
91DGriffin@GPVEC.UNL.EDU http://gpvec.unl.edu Save a Cow …Eat a VegetarianGood Luck To You
92we would love to have you come see us… Thanks for having me … &we would love to have you come see us…...whereagriculture & all it’s peoplemake a difference
94Comparison 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/LMIC90: 2 mg/LDrug B: cephalosporin;Cmax: 32 mg/L … T1/2: 2 hr … 24 hr AUC: 27 mg-hr/LMIC90: 4 mg/LWhich is the “better” drug?Fluoroquinolone: 24 hr AUC:MIC90 = 70/2 = 35Cephalosporin: %T>MIC90 = 6 hr/8 hr interval = 75%Therefore, in this case …cephalosporin is superior to the quinolone
95Comparing Antimicrobial Activity In Vivo Comparing MICsAssumes similar pharmacokineticsAssumes similar pharmacodynamics(apples vs. oranges)Comparing MICs vs. “breakpoints”Crude estimatesAssumes higher breakpoint/MIC ratio is betterComparing PK/PD measures
96Establishing MIC Breakpoints Breakpoint established arbitrarily =>Drug used clinically =>Breakpoint revisedAppropriate PK/PD identified for class =>Magnitude of PK/PD for efficacy established =>Antibiotic PK profile measured =>
102Antimicrobial ModelSuccessful treatment of infection involves the interactions of host, drug and bacteriaHostDrugBacteria sPharmacokineticsTissue penetrationSusceptibility of pathogensPK/PD relationshipPAEKilling rateOther metricsImmune system?The factors not being considered may represent potential limitations.
103Appropriate Pharmacokinetic/Pharmacodynamic Measures to Assess Antimicrobial Activity In Vivo DrugConc -Cidal ActivityPAEPK/PD MeasuresBeta-lactamFixedMinimalT>MICMacrolideSomeAzalideLongerAUC:MICAminoglycosideLinear
104Please know,We take our responsibility to use antibiotics properly very seriously …