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