IFT Review of Antibiotic Resistance - Federation of Animal Science ...

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IFT Review of Antibiotic Resistance - Federation of Animal Science ...

Antimicrobial

Resistance:

Implications for the Food System

An Expert Report

IFT Foundation

Sponsored by the


Intellectual Contributors

Frank Busta

University of Minnesota

Bruce Cords

Ecolab

Scott Hurd

Director, WHO Collaborating Center

for Risk Assessment and Hazard

Identification in Foods of Animal Origin

Richard Isaacson

University of Minnesota

Michael Davidson

University of Tennessee

Karl Matthews

Rutgers University

Michael Doyle, Panel Chair

University it of Georgia

John Maurer

University it of Georgia

John Hawke

Louisiana State University

Jianghong Meng

University of Maryland


Intellectual Contributors

Thomas Montville

Rutgers University

Anne Vidaver

University of Nebraska

Thomas Shryock

Elanco Animal Health

Lyle Vogel

American Veterinary Medical Association

John Sofos

Colorado State University

IFT Staff: Jennifer McEntire

Rosetta Newsome

Fred Shank


Incidence of Foo

dborne Illness in

United States

● U.S. Centers for Disease Control and Prevention

estimates 76 million cases of foodborne illness

annually

▲ Includes 325,000 hospitalizations and 5,000

deaths

P. S. Mead et al. 5:607 (1999)


Leading Bacterio

logical Causes of

Enteric Foodborne Illness in USA


Campylobacter jejuni –estimated 2.4 million cases/yr

● Salmonella sp. – estimated 1. 4 million cases/yr

● E. coli O157:H7 – estimated 73,000 cases/yr

P. Mead et al. Emerging Infect.

Dis. 5:607-625 625 (1999)


Principal Source

es of Foodborne

Pathogens

Animals used in food production

▲ Cattle – E. coli O157:H7 (EHEC), Salmonella,

Campylobacter

▲ Swine – Salmonella, Campylobacter

▲ Poultry – Campylobacter, Salmonella


Antimicrobials

Used in Food

Production and Food Processing

● Important to reduce and control foodborne

pathogens in animals use

ed for foods and the further

processing of animals


Antibiotic Applications


Antimicrobials used during food production and manufacturing to improve the efficiency of

the system, and increase the safety and quality of the product

Animal Husbandry in USA – Antibiotics

♦ Poultry – 8.4 billion broilers and 26

64 million turkeys (2004)

■ 10,000 – 20,000 broilers per house and 5,000 – 10,000 turkeys per group

♦ Swine – 103 million hogs slaughtered for food (2005)

■ >75% of swine grown in operations with >5000 head

♦ Beef Cattle – 37 million head slaughtered (2004)

■ Ca. 83% of feedlots use ≥1 antibiotic for disease prophylaxis or to increase

feed efficiency

♦ Dairy Cattle – 9.12 million head in milk production (2001)

Antibiotics used to treat mastitis

♦ Veal Calves – raised individually in

stalls until 16-18 weeks of age

Antibiotics used to treat respiratory and gastrointestinal diseases and for

disease prophylaxis

Antibiotic uses:

Therapeutic, including subtherapeutic to prevent disease or control pathogens (ca.

95% of antibiotic usage)

Non-therapeutic uses: Promote growth rate and feed efficiency


Antibiotic Applications

▲ Aquaculture – Antibiotics only used in U.S. to treat

disease; not for growth promotion

♦ 49 million pounds of salmon, 20 million pounds of

tilapia, 10 million pounds of striped bass (USA, 2000),

630 million pounds of catfish, 46 million pounds of

trout (USA, 2003)

♦ Catfish grown in 10- to 20-acre ponds with 10,000

fish/acre

▲ Plant Agriculture – Antibiotics to control bacterial

diseases and fungicides to

control fungi

♦ Fruit trees account for most of antibiotic i use on plants

♦ Most antimicrobials used on plants are fungicides

▲ Human Medicine – Antibio

otics used to treat disease and

prevent infection


Antibiotic Usage Data


Exact amount of antibiotics used in animal production is

unknown but likely comparabl

e to amount used in human

medicine

Animals – est. 21.7 million

use; 2004)

pounds (95% for therapeutic

▲ Aquaculture – 65,000 pounds annually (2003)

▲ Plants – 52 million pounds

of fungicides id and 44,000

pounds of antibiotics (2004)

▲ Human – unknown (est. 4.

5 million to 32 million pounds

depending on organizationn providing estimates)


Monitoring Antibiotic Resistance


National Antimicrobial Resistance Monitoring System for

Enteric Bacteria (NARMS)

▲ U.S. antibiotic resistance monitoring system for foodrelated

bacteria – CDC, FDA, USDA

▲ Purpose – monitor change

es in susceptibilities of zoonotic

pathogens in humans, animals and animal products

♦ Bacterial isolates from human and animal clinical

specimens, healthy farm

animals, and raw foods of

animal origin

■ Salmonella, E. coli,

Campylobacter, Enterococcus

♦ Determine Minimal Inhibitory Concentration (MIC) of

important antimicrobial classes used in human and

animal medicine


Trends in Percentage of Antibiotic-Resistant Salmonella Newport

Isolated from Human Cases, a Animals and Animal Products, b and

Retail Meats c in the United States

Antibiotic Resistance

Humans

1996 2001

None of 14 agents 82 65

5 or more agents 6 27

8 or more agents 4 25

MDR-AmpC 0 25

Ciprofloxacin 0

Ceftiofur 4 27

Ampicillin 6 29

Tetracycline 8 30

Trimethoprim-Sulfa 4 2

a

CDC NARMS

b

USDA NARMS

c

FDA NARMS

Animals & Products

Retail

Meats

2002 2000 2002 2003 2002

73

23

22

22

0 0 0 0 0

22 75 78 74 62

24 76 80 74 62

25 78 83 77 62

4 19 2 0


Changes in the incidence of foodborne illness, and corresponding changes in

prevalence of antibiotic-resistant foodborne pathogens in U.S.

Year(s)

Organism

Case rate

(per 100,000)

Relative

Decrease

or increase

%

Resistant

Case rate

(per 100,000)

Relative

decrease

or increase

1996-98 Salmonella 15.9

31% (2 or more 4.9

antibiotics, 1996)

2004 14.7 8% decrease 16% (2 or more 2.4 51%

antibiotics, 2002)

decrease

1996-98 Salmonella

4.9

34% (ACSSuT, 1996) 1.7

Typhimurium

2004 29 2.9 41% decr

rease 21% (ACSSuT, 2002) 06 0.6 65%

decrease

1996-98 Salmonella

1.2

8% (2 or more

0.1

Newport

antibiotics, 1996)

2004 1.7 41% increase

25% (2 or more 0.4 300%

antibiotics, 2002)

increase

1996-98 Campylobacter 18.7

13% (ciprofloxacin 2.4

resistance, 1997)

2004 12.9 31% decrease

20% (ciprofloxacin 2.6 8% increase

resistance, 2002)


Relative rates compared with 1996-1998 baseline period of laboratory-

diagnosed d cases of infection with th

he six most commonly isolated

Salmonella serotypes, by year – Foodborne Disease Active Surveillance

Network, United States, 1996-2006


Risk Factors for Human Infection by

Antibiotic-Resistant Foodborne Pathogens



Very few data regarding food animal-to-human transfer of

antimicrobial resistance to indicate more frequent or severe

infections or increased morbidi

ty and mortality

Antimicrobial therapy is not necessary for recovery from most

cases of foodborne illness

▲ Most foodborne pathogens

self-limiting limiting symptoms that

typically cause mild to moderate

resolve without treatment


Risk Factors for Human Infection by

Antibiotic-Resistant Foodborne Pathogens


Most frequently identified risk factor for infection with antibiotic-resistant

bacteria is prior exposure to antibiotics, including taking antibiotics for

reasons other than foodborne illnesses



Other risk factors are essentially the same as those for acquiring

infections with antibiotic susceptible pathogens, which include:

♦ Age (less than 5 or greater th

han 50)

♦ Pregnancy

♦ Immunosuppression (chemotherapy, HIV infection, other illness)

♦ Reduced liver or kidney funct

tion

Reasonable assumption the risk of treatment failure in immuno-

microbial infections

would be elevated

compromised individuals with antibiotic-resistant



Impact of Antibiotic

cUse Use, Non-Use, and

Resistance

Human Health

▲ Loss of treatment options or treatment failure for individuals seriously ill

from antibiotic-resistant foodborne pathogen

♦ Estimated that 40 – 50% of ho

spitalized patients with salmonellosis

are treated with antibiotics

▲ Longer duration of illness when infected with antibiotic-resistant pathogen

♦ Patients infected with fluoroqu

inolone-resistant C. jejuni j had longer

duration of illness than patients

infected with fluoroquinolone-sensitive

strains

▲ Individuals infected with MDR microorganisms more likely to be

hospitalized than those infected wi

th antimicrobial-sensitive strains

▲ Denmark study found death rates from MDR or quinolone-resistant cases

of salmonellosis were 5 to 10 times

greater than general population

▲ In general, e there e is increased seve

erity of illness associated ated with infections

caused by antimicrobial-resistant pathogens


Impact of Antimicrobi

ial Use, Non-Use, and

Resistance


Trade



Difference among big U.S. trading partners (e.g., Canada and South

Korea) and its competitors (e.g.,

EU) in acceptable use of specific

antibiotics for growth promotion

♦ EU prohibits in feed for growth promotion use of antibiotics that are

used in human medicine

GAO reports to date antimicrobial resistance of microbes associated

with antibiotic use in animals has

not significantly affected U.S. trade in

meat products

♦ GAO indicates this issue may

be a factor in the future, such as in

EU which is phasing out by 2006 use of all antibiotics for growth

promotion


Impact of Antimicrobi

ial Use, Non-Use, and

Resistance


Economic



A ban or partial ban on antibiotics

in food animal production would

increase costs to producers, decr

rease production, and increase retail

prices to consumers

♦ Example, GAO (2004) estimated the elimination of antibiotic use in

pork production would increa

ase producer costs from $2.76 to $6.05

per animal; increase consumer costs for pork from $180 million to

$700 million per year

■ Greatest financial a impact

at producer level

e

Economic assessment of consequences of use in human medicine are

essentially nonexistent


Impact of Antimicrobi

ial Use, Non-Use, and

Resistance


Environmental



Risks to human, animal or environmental health from the direct impact

of antimicrobials on bacteria in aq

quatic and terrestrial environments

appear low

♦ However, antimicrobial agents in ecosystems can lead to drastic

alterations in biodiversity of affected ecosystems, reduction of

microorganisms susceptible to agents, and development of

antimicrobial resistance

Overall, general e lack of knowledg

ge and agreement e about the frequency

and extent of occurrence, fate, and effects associated with

antimicrobials entering the environment. It is difficult to assess

environmental impact of use of antimicrobials.


Management of Antim

microbials to Control

Resistance


Responsible Use



Guidelines exist for responsible use of antibiotics in veterinary and

human medicine

♦ Not merely reduced use because drugs offer valuable benefits

when used appropriately

■ Involves prescribing antim

microbial therapy only when it is

beneficial to the patient, targets therapy to desired pathogens

and use of appropriate drug, and confines treatment duration

Intent is to promote appropriate use of antibiotics, maximizing

efficiency and minimizing resistance development


Risk Analysis for Regulatory Decisions

on Antibiotic Usage


Regulatory environment in US

SA is geared toward protecting

ti

the public from additional risk without consideration of

benefits, hence emphasis on risk assessment

▲ Not possible for regulatory

agencies to judge between the

benefits of antibiotic use for livestock and risks to the

public

♦ Therefore, regulators must reject any practice that

appears to produce an apparent risk unless a

demonstrated higher risk would appear upon rejection

of the practice


Risk Analysis for Regulatory Decisions

on Antibiotic Usage

▲ Example, evidence that t there are significant ifi human health

benefits from antibiotic use

to prevent food animal disease

♦ Subclinical disease infl

uences levels of Salmonella and

Campylobacter contamination of poultry carcasses

■ Therefore, the risk of antibiotic use to control

subclinical disease more than compensates for the

human health benefit

−Estimate that at

least 40,000000 illness-days per

year are prevented by continued use of

virginiamycin to reduce bacterial illnesses in

chicken flocks


Risk Analysis for Regulatory Decisions on

Antimicrobial i Us

sage: Example of

Unintended Consequences?


Risk management action in Europe to eliminate use of

antibiotics for feed efficiency and growth promotion may have

resulted in increased intestinal disease in animals and

concomitant use of more therapeutic antibiotics with resultant

increase in resistance

Resistance among some pathogens (tet R S. Typhimurium,

amp R S. Typhimurium, tet R C. jejuni, cry R C. jejuni, amp R E.

coli) have increased in Europe


Risk Analysis for Regulatory Decisions on

Antimicrobial i Us

sage: Example of

Unintended Consequences?

▲ Example, Denmark banned in 1998 use of antibiotics for

growth promotion of animals

♦ Total use of antibiotics in

animals in Denmark

decreased 30% between

1997 (before ban) and 2004,

there was a 41% increase in therapeutic ti uses between

1999 (after ban) and 2004

■ Between ee 1999-2004,

tet R and amp R of S.

Typhimurium from pigs increased, from chickens

increased from 0% in

1997 to 17% in 2004 and from

ill humans increased

from 18% to 46%


Risk Analysis for Reg

gulatory Decisions on

Antimicrobial Usage


EU banned antibiotic use in feed for growth promotion on the

basis of the precautionary principle which is employed when

scientific information is insuffici

ient, inconclusive or uncertain

▲ Sweeping risk management

measures that are proposed

for a certain classification of

use (e.g., growth promotion)

can be draconian and without predictable results

▲ Analysis would best be carried out on a case-by-case basis

and driven by product-spec

ific, science-based risk

assessments


Risk Analysis – Expe

ert Panel Conclusion


Expert Panel concludes that thorough risk assessments

should be used to guide selection of risk management actions

so that unintended consequenc

ces are minimized


Conclusions



Antibiotics are integral to food production, providing for good

physical condition of crops and

good health of food animals

Antibiotics are used to treat, prevent and control disease

among food animals and also improve feed utilization

▲ Despite the utility of antibiotics in agriculture, the trend is to

reduce usage because of use for any purpose selects for

resistance


Conclusions


Antibiotic resistance among foodborne pathogens may create

an increased burden to human

health in the following ways:

1. Resistant t pathogens contam

minating food animals have the

potential to reach humans

2. Human use of antibiotics may increase the risk of acquiring

an infection with an antimicrobial resistant pathogen

3. Human infection with a resistant microbe may limit illness

treatment t t options

4. Antibiotic-resistant foodborne pathogens may develop

increased virulence


Conclusions




Antibiotic-resistant intestinal bacteria may be present in food

animals, regardless of exposure of the animals to an antibiotic

Interventions that effectively reduce the prevalence of

foodborne pathogens also reduce the prevalence of those that

are resistant t to antibiotics

Food scientists can influence preventing the spread of

antibiotic-resistant (and sensitive) foodborne pathogens by

preventing them from entering the food supply and, if present,

inactivating them or preventing

their growth


Conclusions


Selective pressure for the development of antimicrobial

resistance occurs in the food system from production to

processing, and in human med

dical use

▲ Given the different resistance mechanisms, conditions

selecting for resistance, and

dissemination patterns of

resistant microorganism, a single approach to address

the resistance issue to maximize the benefit of

antimicrobials for society

is not possible


Conclusions


Qualitative and quantitative risk

assessments are being used

to determine transfer of antibiotic resistance through the food

chain resulting in human health

h consequences

▲ For many antibiotics such as tylosin, tilmocosin, and

virginiamycin used in food animals, the estimated risk to

human health is small

▲ However, fluoroquinolone used to treat poultry disease

through water was deemed

by FDA as an unacceptable

risk to human health and was withdrawn


Conclusions




Antibiotic-resistant intestinal bacteria may be present in food

animals, regardless of exposure of the animals to an antibiotic

Interventions that effectively reduce the prevalence of

foodborne pathogens also reduce the prevalence of those that

are resistant t to antibiotics

Food scientists can influence preventing the spread of

antibiotic-resistant (and sensitive) foodborne pathogens by

preventing them from entering the food supply and, if present,

inactivating them or preventing

their growth


Conclusions


Risk management strategies to

minimize and contain antibiotic-

in place all along the food

chain, but can be improved

resistant foodborne bacteria are

▲ The strategies implemented

include use of antibiotic

alternatives, implementation

n of judicious or prudent

antibiotic use guidelines, and implementation of national

resistance monitoring programs


Conclusions


Regulatory targeting ti of specific antibi

iotic-resistant i t t foodborne pathogens

may not be the most successful or cost-effective means to reduce overall

foodborne illness




A HACCP approach applied throughout the food chain is considered

d

the most effective measure to controlling foodborne pathogens and

thereby reducing foodborne illnesses

Most interventions, ti critical contro

l points to kill or reduce foodborne

pathogens are equally effective in

controlling microbes regardless of

their resistance to antibiotics

Applying interventions ti to critical foodborne pathogens in general rather

than focusing on antibiotic-resistant strains specifically would have the

greatest impact in reducing foodborne illnesses


Specific Recommendations


The IFT Expert Panel concluded the following areas warrant attention or

investigation:




The public health benefits as wel

l as the risks of losing the efficacy of

existing and future antimicrobials must be considered

The public health impact of antimicrobial resistance should be

determined on the basis of risk as

ssessment, and resistance should be

considered on the basis of an individual microorganism exposed to a

specific agent under a specific condition of use

Risk management age e strategies es sho

uld be guided by the results of risk

assessments


Specific Recommendations



Prudent use of antimicrobials should be practiced to limit

resistance selection and maintain maximal benefit. Prudent

use does not necessarily corre

late with reduced use; an

unknown risk of maintaining use may be less than an equally

unknown risk of reducing use

Prudent use guidelines for antibiotics should be further

developed


Specific Recommendations




Effective alternatives ti to antibiot

tics should be explored

Surveillance program and food attribution models should be

explored as means for measuring the effectiveness of the food

industry’s microbiological interventions

The relationship of the use of specific antibiotics in food animal

husbandry to resistance selection rates among major

foodborne bacteria at slaughter

should be determined and

compared between farms where antibiotics are used and

farms where antibiotics are not

used


Specific Recommendations


Although it needs to be confirmed, information available to

date indicates that validated microbial interventions used in

food processing and in the hou

use are equally effective for

antimicrobial-susceptible and resistant microorganisms and

should be used to prevent dissemination of foodborne

pathogens


Web Site Address for Complete Report

Comprehensive Reviews in Food

Science and Food Safety

http://members.ift.org/IFT/Pubs/CRFSFS/


MPD’s Additional Perspective

● ca. 15% of foods consume

ed in U.S. is imported

▲ 83% of fresh and frozen

seafood and fish

♦ Most shrimp is aqua

cultured in Southeast Asia

▲ 45% of fresh fruits

▲ 16% of fresh vegetables

● Indiscriminant use of antibiotics in food production in

some developing countries

● Bottom line: Imported foods from some countries are

likely to be important sourc

ces of MDR microbes



MDR Salmonella Paratyphi B var. Java

Outbreak

in Cattle

MDR S. Java outbreak occurredincattleintheUnited

the Kingdom

▲ MDR S. Java associated with tropical fish from Thailand

put in cattle drinking water

tanks to control algae

♦ Thailand aquaculture does not normally apply

antibiotics directly to ponds

■ Fish are fed chicken

manure and chickens are fed

antibiotics

Antibiotics induc

cing drug resistance likely

present in chicken feces fed to fish

John Threlfall, Society for General Microbiology Annual

Meeting, Edinburgh, Scotland, April 2005


Food Safety Trends – Food Imports

● Increased importation of foods and food

ingredients

▲Includes from countries having production

and processing cond

ditions below U.S.

standards


China as Example

of Questionable

● Issues

Food and Food Ingredient Source

▲ Farmers rely on heavy use of chemicals to deal

with pest pressures, and

antibiotics are widely used

to control disease in livestock, poultry and

aquaculture

♦ Use many highly toxic pesticides, including

some that are banned in U.S.

♦ Farm chemicals are sometimes mislabeled and

inappropriately used

http://www.ers.usda.gov/AmberWaves/November06/Features/FoodSafety.htm


China as Example

of Questionable

Food and Food Ingredient Source

♦ Some farmers have

little understanding of

correct chemical use, resulting in excessive

residues in harvested product

♦ Industrialization and

lax environmental

controls contribute

t

to heavy metal

contamination of foods


China as Example

of Questionable

Food and Food Ingredient Source

▲ Untreated human and animal wastes are applied

to fields directly and through irrigation water

♦ Results in food contamination ti with Salmonella

ll

and harmful microorganisms


Examples of U.S. FDA

Detentions of Food and

Food Ingredients from China (February 2007)

Food/Ingredient

Contaminant

Dried Pepper Powder

Ginseng Extract Powder

IQF Pea Pods

IQF Soybeans

Frozen Grilled Eel

IQF Breaded Shrimp

Salmonella

Pesticides

Pesticides

Pesticides

Veterinary Drugs

Veterinary Drugs


Examples of U.S. FDA

Detentions of Food and

Food Ingredients from China (March 2007)

Food/Ingredient

Contaminant

Fresh Ginger

Ground Chili Powder

Ginseng

Mandarin Oranges

Red Melon Seeds

Pumpkin Seeds

Pesticides

Salmonella

Pesticides

Pesticides

Aflatoxin

Salmonella


Examples of U.S. FDA Detentions of Food and

Food Ingredients from

India (March 2007)

Food/Ingredient

Contaminant

Turmeric Powder

Salmonella

Creamy Peanut Butter

Pesticides, Aflatoxin

“Richfield” Creamy Peanut Butter

Pesticides, id Aflatoxin

Pista Burfee Fried Snack Food

Salmonella

All In One Snack Food

Salmonella

Red Chili Powder

Salmonella

Chili Powder

Salmonella

Coriander Powder

Salmonella

Spices – Cumin Whole

Salmonella

Black Pepper

Salmonella

ll

Sesame Seeds

Pesticides


Country of origin of spices imported by the United States,

by weight, for fiscal year 2003

Nation

China

Honduras

Mexico

Lebanon

Peru

India

Chile

Spain

Morocco

Argentina

V. Vij et al. 2006. J. Food Protect. 69

9:233-237

237

Amt (10 9 kg)

237.5

20.9

11.0

3.3

1.3

10 1.0

0.73

0.34

0.32

0.26


Do Not Rely on Federal or State

Food/Ingredient Inspection to Detect

Harmful Microbes or Chemicals

● FDA samples and tests less than 1% of food

imports under its jurisdict

tion

● USDA inspects only ca. 20% of meat and poultry

imports

● Wheat gluten contaminated with melamine from

China used in pet food

▲ Not originally detectedd by FDA


Impact of Wheat Gluten

Incident on Menu Foods

Dr. Doyle,

I recently saw a video on MSN of an interview you did on food

safety. I want to thank you for your accuracy and clear

information about the adulterated Chinese wheat gluten that

has been responsible for the several pet food recalls over the

last 3 weeks.

I am a UGA graduate (BSA 77, MS 79) and am Executive Vice

President of Menu Foods, whichh you correctly referenced as

the first company to identify the

health risk and initiate the

recall. So much of the press has been negative and more

often than not, inaccurate. It was great to see someone who

got it right!


Impact of Wheat Gluten

Incident on Menu Foods

For our efforts in coming forward with the facts we are

looking at $40 million + in dire

ect cost, more than 40 class

action law suits (so far) and a possible congressional

committee hearing. Still we know we did the right thing.

Again, thank you for your clear, professional portrayal of the

situation with food safety and imported food products.

Randall C. Copeland

Executive Vice President, Sales

and Marketing

Menu Foods

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