Dr. Nick Gabler - Evaluation of Antibiotic Alternatives for Nursery Pigs

Department of Animal Science

Evaluation of (Growth Promoting) Antibiotic

Alternatives for Nursery Pigs

Nicholas Gabler, Ph.D.Iowa Pork Congress

January 26, 2017

Introduction• Antibiotics have been used in animal feed for

about 50 years • Anti-microbial agent• Growth-promoting agent and improvement in

performance

• Chlortetracycline, procaine penicillin, oxytetracycline, tylosin, bacitracin, neomycin sulfate, streptomycin, erythromycin, linomycin, oleandomycin, virginamycin, and bambermycins have been common feed additives for livestock and poultry

FDA approved antibiotic use1. Disease treatment

2. Disease control

3. Disease prevention

• Therapeutic use for treating clinically sick animals, preventing or reducing the incidence of infectious disease agents

Kent Schwartz (2016)

FDA disapproved antibiotic use (2017)• FDA medically important antibiotics

• Same, or in same classes, as antibiotics used to treat humans

• Possible exceptions• Bacitracin• Mecadox?• Narasin• Bambermycin• Tiamulin

• Growth Promotion or Improvement of Nutritional Efficiency

• Increasing feed efficiency

• Improving growth rates

• Antibiotic growth promoters (AGPs)

• Administered at a low, sub-therapeutic dose

Guidance for Industry #209• “Production uses” (growth promotion and

nutritional efficiency) of antibiotics in classes used in human medicine are injudicious

• Requires the use of these classes of antibiotics be under “veterinary oversight”• “Judicious use”

AGPs• All swine antibiotics are affected under

Guidance #209

• Exceptions for AGPs for in feed and water use• Bacitracin• Carbadox• Bambermycin• Ionophores • Tiamulin

Potential implications of antimicrobials on animal physiology

• Optimal animal health depends on host and microbial attributes

• AGPs have1) Indirect effects through

the microbiota

2) Direct effects on the host

• The functional and interactive effects of AGPs on the host and the microbiota are less clear

International Journal of Antimicrobial Agents, Volume 49, Issue 1, 2017, 12–24http://dx.doi.org/10.1016/j.ijantimicag.2016.08.006

Department of Animal ScienceInternational Journal of Antimicrobial Agents, Volume 49, Issue 1, 2017, 12–24http://dx.doi.org/10.1016/j.ijantimicag.2016.08.006

AGPs function:B. AGPs may function by

altering the composition of the microbiota to reduce competition for nutrients and/or by reducing pathogen load (bacteria-centric hypothesis)

C. Direct immunomodulatory agents that allow for resources to be shifted to metabolic functions (i.e. host-centric hypotheses)

The intestinal mucosa is a dynamic surface central both to metabolic and immune homeostasis

FEED GRADE AGP ALTERNATIVES STUDY

(PRELIMINARY DATA- ISU/USDA NADC)

M. Schroyen, J. Trachsel, S. Curry, H. Allen, C. Tuggle, C. Loving, E. Burrough, N. Gabler

Post-weaned performance (5 weeks) Diet ADG, kg ADFI, kg G:F Control 0.32a 0.37a 0.88 CTC 0.43b 0.51b 0.85 5% inulin 0.37ab 0.44ab 0.87 5% Resistant Starch (RS) 0.40b 0.46ab 0.87 0.25% Butyrate 0.36ab 0.42ab 0.88

0 1 2 3 4 5 6-1

15Control

5% inulin

0.25% Butyrate

Cecal SCFA

DEVELOPMENT AND VALIDATION OF A STANDARDIZED

SCIENTIFIC PROTOCOL EVALUATING ANTIBIOTIC

ALTERNATIVES IN GROWING PIGS

(NPB# 15-204)

Project Team• Iowa State University

• Nicholas Gabler (AnS)• John Patience (AnS)• Kent Schwartz (VDL)• Chris Rademacher

(VDPAM)• Alex Ramierez (VDPAM)• Daniel Linhares (VDPAM)

• Wes Schweer (AnS)• Kristin Olsen (AnS)

• USDA-NADC• Heather Allen• Crystal Loving

Project Objectives• To develop a framework within which studies on alternatives

to antibiotic growth promotants may be conducted

1. To develop a protocol that defines the critical and essential components that can be used to undertake studies on alternatives of antibiotic growth promoters, such that results will be clear and definitive and can be compared to other studies on the same topics.

• This protocol will have sufficient detail to achieve this objective but also have sufficient flexibility and framework to apply to a broad range of experimental approaches and topics

2. To validate the protocol(s) defined by objective 1 by undertaking a study in nursery pigs to provide data on options for AGP replacement in nursery diets

Proposed outcomes for the NPB• An extensive review of nursery-finisher studies, including

methodologies and designs that will be utilized to construct a standardized experimental protocol that identifies the essential requirements of an effective evaluation of alternatives to AGPs

• The results of a validation study to test the adequacy and efficacy of the proposed standardized protocol

• Data on different approaches to replacing AGPs – i.e. organic acids, pre- or pro-biotics and specific diet formulations.

• The validation phase will not only confirm the validity of the standard protocol but it will also provide useful data on the topic of interest

Search term into database

Remove duplicates, keep only journal articles since 1990

Exclude articles that didn’t contain performance data or mortality in abstract

Keep articles in English with full text available

Search Parameters• Databases used:

• Pubmed• Sciencedirect• Web of Science• CAB Abstracts• Agricola

• Searched all years for initial search

Search ParametersCategory Search TermProbiotic probiotic AND swine(pig)Prebiotic prebiotic AND swineOligosaccharide

oligosaccharide AND swine AND wean

Organic Acids (“organic acid”) OR (“organic acids”) AND swine

Essential oils / botanicals / plant extracts

essential oil AND swinebotanical AND swineplant extract AND swine AND wean

Yeast yeast AND swine AND weanResistant starch/ fiber

starch AND swine AND weanfiber AND swine AND wean

Zinc/Copper zinc AND swine AND weancopper AND swine AND wean

Lysozyme lysozyme AND swine

Search Parameters• Export all references to Endnote

• Exclude papers previous to 1990• Exclude duplicates and keep only research articles

• Read abstracts and keep only articles that report performance data or mortality

• Obtained full text papers written in English

Criteria by which each paper was evaluated

• Challenge (yes/no)• n/trt• Exp. Unit• Pigs/pen• Age of pig (days)• Start BW (kg)• Genetics• Duration of feeding

(days)

• Diet components• ADG (-,0,+)• ADFI (-,0,+)• Feed Efficiency

(-,0,+)• Mortality (-,0,+)• Blood Assay (yes/no)• Tissue Assay (yes/no)• Microbiome (yes/no)

Paper Criteria• If paper included control and multiple

treatments, each treatment considered one experiment

• Example:• Trts: control, butyric acid, propionic acid,

butyric + propionic acid• Paper would include 3 “experiments”

Probiotics• Search term: probiotic AND swine• Total articles: 2,296• After duplicates + since 1990: 1,629• Contain performance/mortality: 288• Articles available: 172• Probiotic type: Bacillus (39), Bifidobacterium

(26), Enterococcus (27), Escherichia (8), Lactobacillus (62), Lactococcus (5), Pediococcus (10), Saccharomyces (12), combo (65), other (5)

Probiotics• 309 total studies• 46 challenge studies• ADG: (+) = 172; 0 = 172; (-) = 5; not reported = 10• ADFI: (+) = 40; 0 = 153; (-) = 10; not reported = 106• GF: (+) = 78; 0 = 134; (-) = 3; not reported = 94• Mortality: (+) = 15; 0 = 28; (-) = 0; not reported =

266• Avg. n/trt: 21.1• Avg. pigs/pen: 6.0• Avg. study duration: 35.9 days• Avg. age: 23.9 days• Avg. BW: 14.2 kg

Probiotic - ADGRespons

studies

Start BW (kg)

Duration

(days)Age

(days)

(0) 172 15.1 29.6 23.9(-) 5 25.7 28.0 44.2(+) 122 12.9 45.7 23.5nr 10 5.0 26.2 17.3

Total 309

Response n/trt Pig/pen

Avg Min

(0) 14.6 2 400 8.0 32.5 4.9 1 22 4.0 4.2(-) 14.0 12 16 15.

01.7 5.8 1 14 4.0 4.9

(+) 18.5 2 600 6.0 58.4 7.3 1 35 6.0 5.6nr 165.

52 147

436.2 8.4 1 11 10.5 4.0

No change in growth

Negative impact on growth

Positive impact on growth

Not reported

Probiotics - Observations• No genetic pattern – 44 genetic

combinations• Of 122 (ADG+):

• 37 probiotic combination• 29 Lactobacillus spp.

• 8/29 = Lactobacillus plantarum• 20 Bacillus spp.• 16 Enterococcus spp.

• 15/16 = Enterococcus faecium

Prebiotics• Search term: prebiotic AND swine• Total articles: 517• After duplicates + since 1990: 440• Contain performance/mortality: 53• Articles available: 39

Prebiotics• 92 total studies• 7 challenge studies• ADG: (+) = 10; 0 = 80; (-) = 0; not reported = 2• ADFI: (+) = 4; 0 = 74; (-) = 1; not reported = 14• GF: (+) = 10; 0 = 60; (-) = 0; not reported = 23• Mortality: (+) = 0; 0 = 3; (-) = 0; not reported = 90• Avg. n/trt: 10.4• Avg. pigs/pen: 3.9• Avg. study duration: 28.8 days• Avg. age: 25.0 days• Avg. BW: 9.9 kg

Prebiotic - ADG

Response

# studie

Start BW (kg)

Duration (days)

Age (days)

(0) 86 9.0 26.0 23.8(-) 0 -- -- --(+) 11 10.9 45.8 21.3nr 2 9.8 19.0 25.0

Total 99

Avg Min

(0) 11 2 71 10.0

8.5 3.8 1 11 4.0 2.4

(-) -- -- -- -- -- -- -- -- -- --(+) 6.8 4 8 7 1.3 4.6 3 10 4.0 2.1nr 6 6 6 6.0 0.0 1.0 1 1 1.0 0.0

Prebiotic – Observations • No genetic pattern – 7 genetic combinations• Diets – 5/11 Corn-soy based• Of 11 (ADG+):

• 3/10 = sorbitol• 3/10 = lactulose

Oligosaccharide• Search term: oligosaccharide AND swine

AND wean• Total articles: 485• After duplicates + since 1990: 376• Contain performance/mortality: 74• Articles available: 44

Oligosaccharide• 92 total studies• 5 challenge studies• ADG: (+) = 17; 0 = 71; (-) = 4; not reported = 0• ADFI: (+) = 6; 0 = 58; (-) = 3; not reported = 3• GF: (+) = 17; 0 = 48; (-) = 0; not reported = 5• Mortality: (+) = 1; 0 = 5; (-) = 0; not reported = 64• Avg. n/trt: 10.3• Avg. pigs/pen: 5.9• Avg. study duration: 30.6 days• Avg. age: 22.9 days• Avg. BW: 7.5 kg

Oligosaccharide - ADGRespons

studies

Start BW (kg)

Duration (days)

Age (days)

(0) 71 5.3 30.4 25.0(-) 4 2.1 22.8 24.8(+) 17 3.6 24.0 18.6nr 0 -- -- --

Total 92

Avg Min

(0) 10.7 3.0 50.0 6.0 11.7 6.0 1.0 32.0 5.0 5.3(-) 7.3 6.0 10.0 6.5 1.6 4.5 1.0 6.0 5.5 2.1(+) 13.4 3.0 50.0 8.0 12.9 7.4 1.0 12.0 10.0 3.6nr -- -- -- -- -- -- -- -- -- --

Oligosaccharide – Observations• No genetic pattern – 8 genetic combinations• Diet – 7/17 Corn-soy based

Organic Acids• Search term: (“organic acid”) OR (“organic

acids”)) AND swine• Total articles: 1,963• After duplicates + since 1990: 1,573• Contain performance/mortality: 130• Articles available: 80

Organic Acids• 154 total studies• 8 challenge studies• ADG: (+) = 44; 0 = 84; (-) = 2; not reported = 0• ADFI: (+) = 17; 0 = 107; (-) = 1; not reported = 5• GF: (+) = 26; 0 = 101; (-) = 0; not reported = 3• Mortality: (+) = 10; 0 = 5; (-) = 0; not reported =

115• Avg. n/trt: 8.5• Avg. pigs/pen: 6.3 • Avg. study duration: 43.8 days• Avg. age: 24.3 days• Avg. BW: 13.0 kg

Organic Acids - ADGRespons

studies

Start BW (kg)

Duration (days)

Age (days)

(0) 104 13.5 43.5 24.3(-) 2 8.1 31.5 25.5(+) 48 14.9 45.6 27.1nr -- -- -- --

Total 154

Avg Min

(0) 10.3

2 168 7.0 18.1 5.9 1 34 4.0 6.1

(-) 7.5 5 10 7.5 2.5 4.0 2 6 4.0 2.0(+) 7.8 3 40 6.0 6.7 7.5 1 20 6.0 5.0nr -- -- -- -- -- -- -- -- -- --

Organic Acids – Observations• No genetic pattern – 24 genetic

combinations• Diet – 26/48 Corn-soy based

Essential oils/botanicals/plant extracts• Search term: plant extract AND swine AND

wean• Search term: botanical AND swine AND wean• Search term: essential oil AND swine• Total articles: 2,608• After duplicates + since 1990: 1,663• Contain performance/mortality: 181• Articles available: 131

Essential oils/botanicals/plant extracts• 334 total studies• 40 challenge studies• ADG: (+) = 74; 0 = 243; (-) = 8; not reported = 9• ADFI: (+) = 34; 0 = 283; (-) = 14; not reported = 44• GF: (+) = 55; 0 = 221; (-) = 6; not reported = 48• Mortality: (+) = 1; 0 = 15; (-) = 1; not reported =

Ess. Oils/Botanicals - ADGRespons

studies

Start BW (kg)

Duration (days)

Age (days)

(0) 243 10.3 32.3 24.1(-) 8 22.5 44.6 22.0(+) 74 11.6 35.6 25.0nr 9 25.2 11.3 66.6

Total 334

Avg Min

(0) 8.1 1 50 6.0 5.6 4.9 1 34 4.0 4.2(-) 13.

85 32 10.

08.8 5.6 1 9 5.5 3.1

(+) 8.3 2 33 6.0 5.4 5.6 1 30 4.0 4.3nr 11.

44 15 12.

02.8 3.6 1 24 1.0 7.2

Ess. Oils/Botanicals - Observations• No genetic pattern – 24 genetic

Yeast• Search term: yeast AND swine AND wean• Total articles: 782• After duplicates + since 1990: 426• Contain performance/mortality: 96• Articles available: 60

Yeast• 87 total studies• 12 challenge studies• ADG: (+) = 22; 0 = 63; (-) = 1; not reported = 1• ADFI: (+) = 12; 0 = 57; (-) = 1; not reported = 17• GF: (+) = 10; 0 = 54; (-) = 1; not reported = 22• Mortality: (+) = 1; 0 = 7; (-) = 0; not reported = 79• Avg. n/trt: 12.0• Avg. pigs/pen: 4.9• Avg. study duration: 25.6 days• Avg. age: 21.2 days• Avg. BW: 8.4 kg

Yeast - ADGRespons

studies

Start BW (kg)

Duration (days)

Age (days)

(0) 63 9.2 22.9 21.6(-) 1 6.6 28.0 22.0(+) 22 6.3 31.0 19.1nr 1 -- 1.0 35.0

Total 87

Avg Min

(0) 10.5 2 64 8.0 8.9 4.6 1 16 4.0 3.7(-) 7.0 7 7 7.0 0.0 5.0 5 5 5.0 0.0(+) 16.3 4 163 8.0 32.4 5.9 1 20 4.0 4.5nr 15.0 15 15 15.

00.0 1.0 1 1 1.0 0.0

Yeast - Observations• No genetic pattern – 16 genetic

Resistant starch/fiber• Search term: starch AND swine AND wean• Search term: fiber AND swine AND wean• Total articles: 2,432• After duplicates + since 1990: 1,352• Contain performance/mortality: 157• Articles available: 81

Resistant starch/fiber• 203 total studies• 10 challenge studies• ADG: (+) = 19; 0 = 148; (-) = 34; not reported = 2• ADFI: (+) = 12; 0 = 148; (-) = 28; not reported = 15• GF: (+) = 14; 0 = 137; (-) = 18; not reported = 34• Mortality: (+) = 2; 0 = 11; (-) = 5; not reported =

Starch/Fiber - ADGRespons

studies

Start BW (kg)

Duration (days)

Age (days)

(0) 148 9.8 32.7 24.5(-) 34 10.4 33.0 29.4(+) 19 8.0 26.7 23.2nr 2 9.8 24.0 40.0

Total 203

Avg Min

(0) 9.6 2 100 8.0 11.6 3.1 1 14 2.0 2.4(-) 6.6 3 20 5.0 4.1 2.5 1 8 2.0 1.9(+) 27.

52 353 11.

076.9 9.6 1 37 4.0 12.1

nr 6.0 6 6 6.0 0.0 1.0 1 1 1.0 0.0

Starch/Fiber - Observations• No genetic pattern – 12 genetic

combinations• Diet – no pattern

Zinc/Copper• Search term: zinc AND swine AND wean• Search term: copper AND swine AND wean• Total articles: 1,953• After duplicates + since 1990: 797• Contain performance/mortality: 167• Articles available: 123

Zinc/Copper• 495 total studies:• 38 challenge studies• ADG: (+) = 211; 0 = 278; (-) = 3; not reported = 3• ADFI: (+) = 129; 0 = 342; (-) = 5; not reported = 19• GF: (+) = 100; 0 = 348; (-) = 3; not reported = 44• Mortality: (+) = 9; 0 = 8; (-) = 0; not reported = 478• Avg. n/trt: 11.7• Avg. pigs/pen: 5.1• Avg. study duration: 30.2 days• Avg. age: 24.5 days• Avg. BW: 7.6 kg

Zn/Cu - ADGRespons

studies

Start BW (kg)

Duration (days)

Age (days)

(0) 278 7.9 28.7 25.2(-) 3 2.6 20.0 12.7(+) 211 7.2 32.6 23.7nr 3 6.9 13.7 20.0

Total 495

Avg Min

(0) 12.7

1 137 6.0 21.1 4.4 1 28 4.0 3.3

(-) 6.0 2 10 6.0 3.3 8.5 4 13 8.5 4.5(+) 10.

61 123 6.0 18.0 6.1 1 21 5.0 4.3

nr 8.0 8 8 8.0 0.0 3.0 1 7 1.0 2.8

Zn/Cu - Observations• No genetic pattern – 47 genetic

combinations• Diet – 140/211 Corn-soy based• Of 211 (+):

• 142 Zn• 24/142 = 3000 ppm• 16/142 = 2500 ppm

• 55 Cu• 11/55 = 250 ppm• 10/55 = 200 ppm

Lysozyme• This enzyme functions by attacking

peptidoglycans found in the cell walls of bacteria

• Especially Gram-positive bacteria

• Search term: lysozyme AND swine• Total articles: 1,618• After duplicates + since 1990: 867• Contain performance/mortality: 16• Articles available: 9

Lysozyme• 9 total studies• 3 challenge studies• ADG: (+) = 4; 0 = 3; (-) = 1; not reported = 1• ADFI: (+) = 1; 0 = 5; (-) = 0; not reported = 3• GF: (+) = 3; 0 = 3; (-) = 1; not reported = 2• Mortality: (+) = 0; 0 = 0; (-) = 0; not reported = 9• Avg. n/trt: 11.0• Avg. pigs/pen: 6.0• Avg. study duration: 22.9 days• Avg. age: 15.0 days• Avg. BW: 6.4 kg

Lysozyme - ADGRespons

studies

Start BW (kg)

Duration (days)

Age (days)

(0) 3 4.9 25.7 9.7(-) 1 5.8 21.0 17.0(+) 4 6.9 24.5 21.3nr 1 -- 10.0 4.0

Total 9

(0) 11.7

6 20 9.0 6.0 2.3 1 5 1.0 1.9

(-) 5.0 5 5 5.0 0.0 4.0 4 4 4.0 0.0(+) 13.

35 16 16.

04.8 10.

54 25 6.5 8.5

nr 6.0 6 6 6.0 0.0 1.0 1 1 1.0 0.0

Lysozyme - Observations• No genetic pattern – 7 genetic combinations• Diet –

• 4/9 Corn-soy based • 3/9 milk/milk replacer

Combined Overall Data - ADG

Response # studies Av. Start BW (kg)

Av. Duration (days)

Av. Age (days)

0 1119 10.1 30.7 24.1(-) 57 12.2 32.6 28.7(+) 498 (29%) 9.7 36.2 23.5nr 24 17.1 16.4 36.9

Total 1698

Max Med

(0) 11.0

1 400 7.0 18.1 4.5 1 34 4.0 4.0

(-) 8.2 2 32 6.0 5.5 3.5 1 13 4.0 2.7(+) 12.

81 600 6.0 35.7 6.5 1 37 5.0 5.3

nr 74.6

2 1471

291.9 3.4 1 24 1.0 5.6

Oligos

ic Acid

zyme (

0102030405060708090

87 8165 73 72 73

0.0 4.9

1.52.4 1.1

11 1434 22 25

2.2 2.2 0.0 2.7 1.1 1.0 0.611.1 1.4

(0) (-) (+) nr

What’s next?• Utilizing pivot tables to identify trends, get

perspective of previous studies• Plan to make Excel file available to search

outcomes

• Identify “good” practices and “must” practices• May not be blanket practices, can vary

depending on product

• Conduct validation study

Conclusions• Great judicious use of antibiotics

• AGP function is poorly understood• More complex than just shifting enteric

microbiota populations or alterations in intestinal integrity

• Could have direct and indirect functions• More comprehensive understanding needed• Testing (evaluation) protocols for AGP

alternatives are being developed to help find effective alternatives

QUESTIONS?

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