Using Antimicrobials Like We Want to Keep Them€¦ · Using Antibiotics Like We Want to Keep Them...

Using Antimicrobials Like We Want to Keep Them

Mike Apley, DVM, PhDKansas State University

Therapy

Prevention Control

RegluationsRegluations

Animal Medicinal Drug Use Clarification Animal Medicinal Drug Use Clarification Act (AMDUCA)Act (AMDUCA)

Regulations published in 1996Regulations published in 1996

Concurrent feeding of feed additives not Concurrent feeding of feed additives not cleared to be fed togethercleared to be fed together

No ELDU in feedNo ELDU in feedTopdressing is the same as feedingTopdressing is the same as feeding

FDA ActivityFDA ActivityRegulation of GMO animalsRegulation of GMO animalsGuidance 209Guidance 209Guidances 152 and 159Guidances 152 and 159CPG for compoundingCPG for compounding

55thth circuit court of appeals decision, July 18, 2008circuit court of appeals decision, July 18, 2008

Comments solicited relative to VFDs (3Comments solicited relative to VFDs (3--2929--10)10)Proposed milk sampling plan for residues at Proposed milk sampling plan for residues at dairies with repeated cull cow residue violations. dairies with repeated cull cow residue violations. (2011)(2011)

Why?

LegislationLegislation

PAMTAPAMTACaliforniaCaliforniaNew YorkNew York

Where do we overlap with the MDs?Where do we overlap with the MDs?

We will talk about use of antimicrobials We will talk about use of antimicrobials that are the same or in the same group.that are the same or in the same group.If there are linked genes in a resistant If there are linked genes in a resistant cassette, then cocassette, then co--selection for resistance selection for resistance is not dependant on mechanism of action.is not dependant on mechanism of action.

Where do we overlap with the MDs?Where do we overlap with the MDs?

FluoroquinolonesFluoroquinolonesOriginally ciprofloxacin (Cipro)Originally ciprofloxacin (Cipro)

Multiple new human fluoroquinolones in the Multiple new human fluoroquinolones in the last few yearslast few years

Very important in human therapyVery important in human therapyAnaerobic and Gram (+) spectrum has been Anaerobic and Gram (+) spectrum has been expanding.expanding.

Oral and injectable therapy in humans Oral and injectable therapy in humans In cattle, we use In cattle, we use

Enrofloxacin (Baytril) Enrofloxacin (Baytril) -- injectableinjectableDanofloxacin (ADanofloxacin (A--180)180) -- injectableinjectable

Where do we overlap with the MDs?Where do we overlap with the MDs?

MacrolidesMacrolides for humansfor humansErythromycin, azithromycin (Zithromax), Erythromycin, azithromycin (Zithromax), clarithromycin (Biaxin), Telithromycin (Ketek)clarithromycin (Biaxin), Telithromycin (Ketek)

MacrolidesMacrolides for cattlefor cattleTylosin (Tylan) Tylosin (Tylan) –– injectable, feedinjectable, feedErythromycin (Gallimycin) Erythromycin (Gallimycin) –– injectable, hard injectable, hard to find or not available anymoreto find or not available anymoreTilmicosin (Micotil) Tilmicosin (Micotil) –– injectable (oral in swine)injectable (oral in swine)Tulathromycin (Draxxin) Tulathromycin (Draxxin) –– injectable injectable

Where do we overlap with the MDs?Where do we overlap with the MDs?

CephalosporinsCephalosporinsHumans use 1Humans use 1stst through 4through 4thth generationsgenerations

33rdrd generation examples: Cefpodoxime (human generation examples: Cefpodoxime (human [Vantin], and companion animal veterinary [Vantin], and companion animal veterinary [Simplicef] labels), ceftriaxone (Rocephin) [Simplicef] labels), ceftriaxone (Rocephin) 44thth generation extendedgeneration extended--spectrum: Cefepime spectrum: Cefepime (Maxipime)(Maxipime)

In cattleIn cattleCeftiofur (Naxcel, Excenel, Excede) Ceftiofur (Naxcel, Excenel, Excede) –– 33rdrd

generation, injectable onlygeneration, injectable only

Where do we overlap with the MDs?Where do we overlap with the MDs?

TetracyclinesTetracyclinesHumans use a much broader range of Humans use a much broader range of compoundscompounds

““first generationfirst generation”” –– tetracyclinetetracycline““second generationsecond generation”” –– doxycycline, minocycline, doxycycline, minocycline, demeclocyclinedemeclocycline““third generationthird generation”” –– glycylcyclines (tigecycline)glycylcyclines (tigecycline)

In cattleIn cattleOxytetracycline, chlortetracycline, tetracyclineOxytetracycline, chlortetracycline, tetracycline

U. S. CTC, TC and OTC Cattle Approval ExamplesU. S. CTC, TC and OTC Cattle Approval Examples

CTC: 0.1 mg/hd per day in calves up to 250 lbs

CTC: 25 - 70 mg/hd per day in calves 250 – 400 lbs

CTC: 70 mg/hd per day in growing cattle over 400 lbs

CTC: 350 mg/hd per day in beef cattle under 700 lbs

CTC: 0.5 mg/lb per day in beef cattle over 700 lbs

CTC: 350 mg/hd per day in beef cattle

CTC: 400 g/ton to provide 10 mg/lb per day in calves up to 250 lbs

CTC: 10 mg/lb BW for up to 5 days

OTC: 0.5 to 2.0 g/hd per day

Feed efficiency/Rate of gain Prevention/Control Treatment

TC: 22 mg/kg for 3-5 days in calves

These are not all of the CTC, TC, and OTC indications, but are selected to illustrate the regimen range.

Where do we overlap with the MDs?Where do we overlap with the MDs?PhenicolsPhenicols

Chloramphenicol in humansChloramphenicol in humansFlorfenicol (nuflor)Florfenicol (nuflor),, a 2a 2ndnd generation generation derivative, used in cattlederivative, used in cattle

AminoglycosidesAminoglycosidesGentamicin, Amikacin, others in humansGentamicin, Amikacin, others in humansOral neomycin (Biosol) Oral neomycin (Biosol) in cattlein cattle

SulfasSulfasHumans Humans –– primarily potentiated sulfasprimarily potentiated sulfasCattle Cattle –– sulfadimethoxine (Albon), sulfadimethoxine (Albon), sulfamethazine, Sulfachlopyridazine (Vetisulid)sulfamethazine, Sulfachlopyridazine (Vetisulid)

Where do we overlap with the MDs?Where do we overlap with the MDs?PenicillinsPenicillins

Humans Humans Penicillin G and Penicillin VPenicillin G and Penicillin VOxacillinOxacillinAmpicillinAmpicillinExtended spectrum Extended spectrum –– Ticarcillin, PiperacillinTicarcillin, PiperacillinPotentiated Potentiated –– ticarcillinticarcillin--clavulanic acid (Timentin), clavulanic acid (Timentin), ampicillinampicillin--sulbactam (Unasyn), Piperacillinsulbactam (Unasyn), Piperacillin--tazobactam (Zosyn)tazobactam (Zosyn)

In cattleIn cattleProcaine Pen G, Procaine/Benzathine Pen GProcaine Pen G, Procaine/Benzathine Pen GAmpicillin (Polyflex)Ampicillin (Polyflex)Hetacillin (Hetacin K) Hetacillin (Hetacin K) –– converted to ampicillinconverted to ampicillin

No use of the same classNo use of the same class

CarbapenemsCarbapenemsImipenemImipenemMeropenem Meropenem

GlycopeptidesGlycopeptidesVancomycinVancomycin

StreptograminsStreptogramins““SynercidSynercid””Virginiamycin (Vmax, Virginiamycin (Vmax, labeled for cattle and labeled for cattle and swine, but limited use)swine, but limited use)

OxazolidinonesOxazolidinonesLinezolidLinezolid

IonophoresIonophoresIn cattle but no similar In cattle but no similar class in humans, no genetic class in humans, no genetic coco--resistance resistance demonstrated.demonstrated.

BambermycinsBambermycinsAs for the ionophoresAs for the ionophores

Human Resistance ProblemsHuman Resistance Problems

What resistance problems are affecting What resistance problems are affecting humanhuman therapeutics?therapeutics?

Streptococcus pneumoniaeStreptococcus pneumoniaeStaphylococcus aureusStaphylococcus aureus (MRSA, VRSA)(MRSA, VRSA)Salmonella Salmonella Shigella dysenteriaShigella dysenteriaE. coliE. coli

More Human ResistanceMore Human Resistance

Enterococcus faecalis, faeciumEnterococcus faecalis, faecium (VRE)(VRE)Pseudomonas aeruginosaPseudomonas aeruginosaMycobacterium tuberculosisMycobacterium tuberculosisNeisseria gonorrheaNeisseria gonorrheaClostridium difficileClostridium difficileCampylobacterCampylobacter

The Basics of Therapy

Characterization of a disease challengeCase definitionsRegimen designConsistent application of protocolsOutcome evaluation

Treatment ProtocolsTreatment Protocols

First treatment criteriaFirst treatment criteriaTreatment success/ Treatment success/ failure criteriafailure criteriaWhen to apply When to apply success/failure criteriasuccess/failure criteriaManaging singleManaging single--injection injection therapy in the home pentherapy in the home penWhen do you STOP?When do you STOP?

Before you even start deciding which antibiotic…

Case Definitions

Case Definition ExamplesCase Definition ExamplesThese BRD examples need to be These BRD examples need to be characterized as important or misleading characterized as important or misleading criteria.criteria.DepressionDepressionNasal dischargeNasal dischargeOcular dischargeOcular dischargeRumen fill/appetiteRumen fill/appetiteRectal temperatureRectal temperatureLung soundsLung sounds

Lot 8099

First treat failure First treat success

Temp First treat Failure Dead First treat success Case fatality

< 104.0 11 1 0 90.9% 0.0%

104.0 ‐ 104.9 21 7 0 66.7% 0.0%

105.0 ‐ 105.9 24 7 1 70.8% 4.2%

≥ 106.0 19 7 3 63.2% 15.8%

Temp First treat Failure Dead First treat success Case fatality

≤ 104.0 11 1 0 90.9% 0.0%

≥ 104.0 64 21 4 67.2% 6.3%

Days to death:  13, 7, 2, 80

Applying ProtocolsApplying Protocols

Plan your work and work your planPlan your work and work your planDeviating from consistent protocol Deviating from consistent protocol application makes evaluation of outcomes application makes evaluation of outcomes a useless waste of timea useless waste of timeUnderstanding your antibiotic use and Understanding your antibiotic use and outcomes of treatment are criticaloutcomes of treatment are critical

Respiratory Treatment ProgramRespiratory Treatment Program

One antibiotic at a One antibiotic at a timetimeThings that donThings that don’’t helpt help

Routine use of an antiRoutine use of an anti--inflammatory or inflammatory or steroidsteroidAntihistaminesAntihistaminesRevacc at treatmentRevacc at treatmentProbioticsProbioticsVitaminsVitamins

Getting distracted in the treatment shack…

Treatment RecordsTreatment Records Inadequate Treatment Records

Animal ID Trt Date Initials Diagnosis Temp Drug and total dose Comments

1

2

3

4

5

6

7

8

9

10

A Basic Treatment Record

Respiratory ProtocolsRespiratory Protocols

Low riskLow riskHigh riskHigh riskHeavy cattleHeavy cattleAcute Interstitial Acute Interstitial Pneumonia (AIP)Pneumonia (AIP)Tracheal edema Tracheal edema (Honkers)(Honkers)DiphtheriaDiphtheria

GeneralGeneral

Environmental control Environmental control for vaccines/drugs?for vaccines/drugs?NeedlesNeedlesInjection systemsInjection systemsIs everyone trained in Is everyone trained in product product administration?administration?

Injection SystemsInjection Systems

Disinfectants will Disinfectants will inactivate MLV inactivate MLV vaccinesvaccinesDrug residues can Drug residues can interact with other interact with other drugsdrugsOnly enter bottles Only enter bottles with sterile needleswith sterile needles

Realistic Health ExpectationsRealistic Health Expectations

High RiskHigh Risk≥≥ 10% morbidity10% morbidityCase fatality rate 5Case fatality rate 5--10% (or higher)10% (or higher)11stst treatment success treatment success 5050--60%60%

Low RiskLow Risk< 10% morbidity< 10% morbidityCF 1CF 1--2%2%11stst trt success 80trt success 80--90%90%

So, just how much difference So, just how much difference do we make with antibiotics, do we make with antibiotics,

anyway?anyway?

Number Needed to Treat by Disease

9

22(7) 1-8

22(7) 2-40

7(5) 4-30

7(4) 2-5

11(5) 1-3

4(2)3-6

All FOI studies except pinkeye (all papers) and one paper in footrot

# studies (# drugs)NNT Range

Antibiotics at ProcessingAntibiotics at Processing

Treatment for control of Treatment for control of respiratory disease ?respiratory disease ?

Injectable vs. FeedInjectable vs. Feed

Pick your groups for Pick your groups for treatment carefullytreatment carefully

Increasing morbidity

Number of Lots

MassMed Economics

Negative PositiveNeutral

Musculoskeletal DiseaseMusculoskeletal Disease

FootrotFootrotToe and Sole Toe and Sole AbscessesAbscessesUndifferentiated Undifferentiated lamenesslamenessHairy Heel WartHairy Heel WartInfectious arthritisInfectious arthritis

An example where diagnosis makes a big difference in what works and what doesn’t

Typical stance of affected cattle

Typical stance of affected cattle

Biopsy positive for Treponema

Biopsy positive for Treponema

Classic “Strawberry” Hairy Heel Wart lesion, 9-12-05

Erosion extended to front of foot in an advanced case

Using Antibiotics Like We Want to Keep Them

1. Carefully select the animals that will get antibiotics

2. Plan your regimens based on evidence

3. Stick to your plan

4. Evaluate your outcomes with reasonable expectations

5. It’s not just about potential problems in humans, it is about preserving the ability to treat diseases in the animals under our care.