When Your Antibiotic Choice Makes a Difference · When Your Antibiotic Choice Makes a Difference ... regimen pharmacokinetics pharmacodynamics ... regimen in a population of animals

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When Your Antibiotic Choice Makes a Difference

First

What are veterinarians being

asked to do?

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What is “Stewardship”?

2. Is there a non‐antibiotic alternative which will appropriately prevent, control, or treat this disease challenge?

3. Selection of an antibiotic which has been demonstrated to be safe and effective for this purpose

4. Assuring use of the antibiotic as shown to be safe and effective

Yes…

1. Responsibility for appropriate diagnostics and establishment of an accurate and functional case definition

5. Is this antibiotic intervention still necessary?

While…

A difference in treatment outcome based on treating or not treating?

A difference in treatment outcome based on treating with one drug vs. another?

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AnimalDisease Outcome

DiseasePathogen

Location

Antimicrobials

Anti-inflammatory?

diffusionpHions

proteinsbiofilms

susceptibility

virulence

inoculum

age

other disease

genetics

Therapy

total vs. free?

pharmacokineticsregimen

pharmacodynamics

Physiological state

Husbandry

Immunity

diagnostics

case definition

Progression

nutrition

environment

stress

biosecurity

body temperature

hydration

acid/base

production level

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32.1%

53.6%

66.9%

85.9%

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

CCFA Strep Zoo

CCFA all cases

Treated

Control

Treatment successes

Treatment successes Failures

Failures

Horses treated with ceftiofur crystalline free acid (CCFA, Excede®), either all cases treated, or the subset of all cases positive for Streptococcus equi subspecies zooepidemicus (Strep Zoo)

Does CCFA work as well in the Strep Zoo (+) cases as in all cases?

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0% 100%

Clinical success rate according to protocol criteria

(-)

(+) 75%

25%

FailureSuccess Difference attributable to therapy

ARR (Attributable Reduction in Risk) = 75% - 25% = 50%

NNT (Number Needed to Treat*) = 100% / 50% = 2*to make a difference in one animal according to the protocol criteria

32.1%

53.6%

66.9%

85.9%

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

CCFA Strep Zoo

CCFA all cases

Treated

Control

All cases: ARR is 86% - 54% = 32%, NNT is 100%/32% = 3

Strep Zoo (+) subset: ARR is 67% - 32% = 35%, NNT is 100%/35% = 3

Treated successes

Treated successes

Untreated control successes


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32.1%

53.6%

66.9%

85.9%

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

CCFA Strep Zoo

CCFA all cases

Treated

Control

Failures in both groups

Failures in both groups

Difference due to CCFA

Difference due to CCFA



Treated successes

Treated successes

The difference due to the drug (NNT) is the same in the overall group of cases and in the Strep zoo (+) subset. The difference in treatment success is due to the decrease in untreated control success.

Why not just focus on % reduction in failures?• The NNT tells us the actual difference in clinical

outcome due to administering a specific drug regimen in a population of animals with thisdisease.

• The NNT not only reflects the drug efficacy, it also reflects the self cure rate of the population with this disease and the stated criteria for declaring an animal diseased and cured. Note: The cure rate is based on criteria we set, which are

applied equally to the treated and untreated groups.

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DeDonder KD, Apley MD. A review of the expected effects of antimicirobials in bovine respiratory disease treatment and control using outcomes from published randomized clinical trials with negative controls. Vet Clin North Am Food Animal Practice 31 (2015) 97-111

Treatment Success: Controls vs. Treated

Median = 24%

Median = 71%

Median NNT = 2

Median

Upper Quartile

Lower Quartile

Maximum value (excluding outliers

Minimum value (excluding outliers

N = 31 trials

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Mortality: Controls vs. Treated

Median = 17%

Median = 1%

Median NNT = 6N = 25 trials

Morbidity After Treatment for Control of BRD: Controls vs. Treated

Median = 48%

Median = 22%

Median NNT = 5N = 18 trials

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AnimalDisease Outcome

DiseasePathogen

Location

Antimicrobials

Anti-inflammatory?

diffusionpHions

proteinsbiofilms

susceptibility

virulence

inoculum

age

other disease

genetics

Therapy

total vs. free?

pharmacokineticsregimen

pharmacodynamics

Physiological state

Husbandry

Immunity

diagnostics

case definition

Progression

nutrition

environment

stress

biosecurity

body temperature

hydration

acid/base

production level

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Tul Comp ARR NNT

61.8% 32.2% 29.6% 3

81.9% 72.0% 9.9% 10

80.3% 62.8% 17.5% 6

92.9% 77.7% 15.2% 7

67.1% 32.0% 35.1% 3

Median 6

51.0% 25.0% 26.0% 4

53.2% 23.2% 30.0% 3

79.4% 63.6% 15.8% 6

76.5% 53.0% 23.5% 4

73.0% 67.0% 6.0% 17

77.6% 60.6% 17.0% 6

76.5% 43.1% 33.4% 3

87.9% 70.2% 17.7% 6

80.0% 62.5% 17.5% 6

87.8% 74.7% 13.1% 8

Median 6

Tul Comp ARR NNT

0.0% 0.8% 0.8% 125

0.4% 0.8% 0.4% 250

0.8% 1.2% 0.4% 250

0.3% 1.9% 1.6% 63

3.4% 13.6% 10.2% 10

Median 125

6.0% 21.0% 15.0% 7

1.1% 5.1% 4.0% 25

1.0% 0.0% 1.0% 100

0.9% 3.4% 2.5% 40

0.0% 1.0% 1.0% 100

0.0% 3.2% 3.2% 31

0.9% 3.2% 2.3% 43

0.0% 0.0% 0.0% Inf

2.5% 2.5% 0.0% inf

5.6% 10.8% 5.2% 19

Median 42

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N = 98 trials

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Resistance??

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Kansas State Diagnostic Lab isolates


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Tulathromycin % MIC by Year

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Individual Susceptibility Data

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2009 2010 2011 2012 2013

Percent of Isolates ‐Su

sceptible

Oxytetracycline

Tilmicosin

Enrofloxacin

Spectinomycin

Ceftiofur

Florfenicol

0%

10%

20%

30%

40%

50%

60%

0 1 2 3 4 5 6

Percent of Isolates for Given Year

Number of Resistant Interpretations per Individual Isolate

2009 (55)

2010 (155)

2011 (179)

2012 (160)

2013 (240)

Pan‐Susceptible

Multidrug Resistant

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When Your Antibiotic Choice Makes a Difference · When Your Antibiotic Choice Makes a Difference ... regimen pharmacokinetics pharmacodynamics ... regimen in a population of animals