great plains veterinary educational center parts of the puzzle

Great Plains Veterinary Educational Center

Parts of the Puzzle


IBR at work


the role of antibiotics in treating diseases caused by different bugs …

focus on respiratory disease

• Shipping fever / BRD … set up by

lack of immune protectionstress, 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


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.


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


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 …


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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PK / PD Relationships


Antibiotic Movement

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FDA CVM Cephalosporin Update


Cephalosporin Extralabel Prohibition, April 5, 2012

• Response to public’s concern for antibiotic resistance development associated with agriculture use.

• Applies to cattle, swine, chickens, turkeys • Prohibits unapproved dose levels, frequencies,

durations or route of administration• Prohibits use in species in which it is not approved

(does not apply to minor food species)• Prohibits use for prevention purposes


Griffin’s “prevention” vs. “control” use of antibiotic definition

• The use of antibiotic (s) for "prevention” apply to situations in which the “animal or group of animals" might be/would be exposed to a disease causing bacterium/bacteria.

• Whereas the use of antibiotic (s) for "control" would apply to situations in which the “animal or group of animals" have been exposed AND the disease process caused by the bacterium/bacteria as begun in some or all of the group of animals as judged by an understanding of the disease process &/or signs (ex: depression, respiratory aberration, anorexia, etc.) have been observed in animals within the group.


Guidance 209 “The judicious use of medically important antimicrobial drugs in food producing animals”, April 11

• Focus is not to ban, but on assuring drugs are used judiciously … use is a driver of resistance

• “Medically Important Drugs”: GFI # 152 … penicillins, tetracyclines, aminoglycosides, macrolides, streptogramins and lincosamides … Not affected: bambermycin, bacitracin, ionophores

• Phase out none therapeutic (growth promotion) use and phase in veterinary oversight for prevention, control and treatment


Draft Guidance 213 … “Road Map” of how to attain guidance 209, including a timeline, April 11, 2012

• GFI # 152: relative importance to medical community and the duration of use

• Remove growth promotion from all antibiotics• Prevention use must be targeted at defined at-risk

population (timing), a defined dosing duration & effective dosing levels

• Implementation three year target for phasing in changes … Implement revised VFD requirements


Veterinary Feed Directive (VFD) … target the movement of OTC to Rx or VFD

• VFD requirements will be changed … to become less onerous on veterinarians & to allow access to underserved livestock producers

• Redefine: VFD form, VFD transmission, VFD record requirements & VFD VCPR requirement

• Category 1 not withdrawal, Category 2 those with a withdrawal • Broaden(more flexible) animal identification requirement, number

of animal, amount of feed, & expiration of VFD (up to six months) • VCPR (current 21 CFR 530) ... to … “veterinarian may only issue a

VFD for use in animals under their supervision or oversight in the course of their professional practice, and in accordance with all applicable veterinary licensing and practice requirements”


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 work3) antibiotics role in treating diseases caused by different

bugs4) antibiotic classes … and what makes them different5) why an antibiotic seems to work on some cattle & not

others6) how the other things we give sick cattle can influence

an antibiotic's effectiveness7) how to select a proper antibiotic for different diseases8) how to know when to switch9) which antibiotic would make a better choice when you

need to switch if an animal doesn't respond10) when to quit

http://gpvec.unl.edu

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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 ???


Select appropriate high quality products

• Most commonly, BRD has a head start in high-stressed young commingled cattle.


Prevention … is key Treatment salvages only part of the loss

• Immune preparation•Treatment timing


Vaccine Titers


Dealing With DiseaseDon’t let your thermometer do your thinking!

Temp Day 1(Aug AM)

Ave = 105.0SD = 1.8

0.0

2.0

4.0

6.0

8.0

10.0

12.0

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2

Appetite & Depression


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


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)


“May Help … What It Don’t Hurt”


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


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


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 !


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


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.


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.


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???


Prevention … is key Treatment salvages only part of the loss

• Immune preparation•Treatment timing


Dealing With DiseaseDon’t let your thermometer do your thinking!

Temp Day 1(Aug AM)

Ave = 105.0SD = 1.8

0.0

2.0

4.0

6.0

8.0

10.0

12.0

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2

Appetite & Depression

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• Hit the bulls eye with … DART

Þ DepressionÞ AppetiteÞ RespirationÞ Temperature

& never let the thermometer do your thinking!



• Number one rule: ...Have plenty of timeearly every morning ....If the temperature is going to be over 80 F that day ...... Be finished by 10AM

• RELOOK AT CATTLE OFTEN


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


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


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 !


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.


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.


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

It seems to me, we should see visible improvements in attitude & appetite within 96 hrs with the long T1/2 antibiotics …

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http://gpvec.unl.edu [email protected]

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Responsible Use Considers

RESIDUE AVOIDANCE

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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.’

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Something is going

WRONG …

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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

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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.

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• 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

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• 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

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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.

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Total Cattle Marketed

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Residues … Flunixin


Residues … Sulfas


Residues … What were they thinking?


Residues … beta lactams


Residues … OTC vs Vet Rx

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Chemical Defects … Residues1982, just under 2% of all beef cattle 2010, random samples: Zero antibiotics

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High Risk TARGETEDSamples have residue rates that are very low! …

BEEF IS BEEF … & 0.000 positive % …

IS NOT ZERO


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.)

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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?7373

Great Plains Veterinary Educational CenterJune 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)

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“How often do you look at your clients written treatment records?”

June 200775

Vet Survey Materials & Methods (AABP, June 2007)

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“How often do you think producers will not comply with instructions & will cause a violative residue?”

June 200776

Vet Survey Materials & Methods (AABP, June 2007)

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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 77 7777


RESIDUE AVOIDANCE

… Carefully evaluate your ELDU & the extended withdrawals you assign.

… Review treatment & marketing records to assess prescription

compliance.

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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.

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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 & NeoPremiTest (DSM Corp), PHAST (Pre-Harvest Antibiotic Screening Test)

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

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PHAST (B. meg. FAST used on urine)

“This little cow gets to go to

Market”

“This little cow

stays home”

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B. stearothermophilus DSM PremiTest, Charm KIS,

147⁰F (64 ⁰C) for 3 hrs

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Great Plains Veterinary Educational Center84 84

All positive screening tests are confirmed by approved analytical

methods in an FSIS laboratory 84


What is the most important position our profession & industry can have?

DON’T SEND CATTLE

TO MARKET WITH A RESIDUE!

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In the world of food Consumers Purchase

BUY WHAT THEY TRUST

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great plains veterinary educational center parts of the puzzle

Documents

work slide

puzzle slide

little defense slide

normal body cells

different mechanisms

white blood cells

lung lungs cells

late stage of inflammation