Bacterial Antimicrobial Resistance – A Global Issue

David G. White, Ph.D.U. S. Food and Drug Administration

1944

Words of CautionAlexander Fleming warned in 1945 that misuse and overuse of penicillin could lead to the selection and propagation of resistant bacterial mutants

In fact, just a few years after the introduction of penicillin in 1946, penicillin-resistant staphylococci appeared

The sample of Penicillium can now be found in the Science Museum, London

There are > 100 antibacterial agents currently approved for use in clinical

medicine

However, resistance has followed each new antibiotic, albeit with

varying time and frequency

The Origin of Species by Means of Natural Selection, 1859

Charles Darwin

His theory of evolutionary selection holds, simply, His theory of evolutionary selection holds, simply, that variation within species occurs randomly and that variation within species occurs randomly and that the survival or extinction of each organism is that the survival or extinction of each organism is determined by that organism's ability to adapt to determined by that organism's ability to adapt to

its environmentits environment

““Survival of the FittestSurvival of the Fittest””

Drug Resistance Equation

Resistance gene(s) in bacteriaResistance gene(s) in bacteria

+ +

Antimicrobial (selective agent) Antimicrobial (selective agent)

AntimicrobialAntimicrobial--resistant bacteriaresistant bacteria

Environment

Environment

Dissemination of Antimicrobial Resistance

Humans Animals

Bacteria

Food,Water

Dissemination of Antimicrobial Resistance

Adapted from Witte, W. 2000. IJAA. 14:321-325

Antibiotic usefor growth promotion,

prophylaxis, and therapy

Foodanimals

Main reservoirsSelective pressures

Hospitalizedpatients

Community

Antibiotic use for

therapy andprophylaxis

Hospital admission

FecesMeat

Products

Feces

Slurry

Food

SoilCulture plants

Surface water

Waste water

Animalfeed

Microbial Gene Exchange

Dissemination of Streptothricin Resistance in E. coli

OriginOrigin 19821982 19831983 19841984 19851985 19861986 19871987

PigsPigs -- ++ ++ ++ ++ ++Farm PersonnelFarm Personnel -- -- ++ ++ ++ ++Farm FamiliesFarm Families -- -- ++ ++ ++ ++CommunityCommunity -- -- -- ++ ++ ++Community Community UTIUTI’’ss -- -- -- ++ ++ ++S. S. sonneisonnei -- -- -- -- -- ++

From: Witte, W. 1997. Antibiotic resistance, Ciba Foundation SymFrom: Witte, W. 1997. Antibiotic resistance, Ciba Foundation Symposium 207posium 207

NourseothricinNourseothricin introduced in animal feed in 1983 in former East Germanyintroduced in animal feed in 1983 in former East Germany

The Biology of Antimicrobial Resistance

Selection pressure – Survival of the fittestResistance precedes the use, and in some instances the discovery, of antimicrobial agentsHistorically, resistance emerges incrementally from low- to medium- to high-levels

Less true today, with MDR mobile DNA elements

Resistance typically develops from single to multiple antimicrobialsUpon removal of the use of a drug, the persistence of resistant phenotypes or return to a state of predominantly susceptible phenotypes in a population is uncertain

Worldwide Resistance by Select Bacterial Pathogens

Source: Fritsche, T. R., et al., Antibiotics in Laboratory Medicine, 5th Ed., 2005

1997 1998 1999 2000 2001 2002MRSA 2,531 29.2 36.6 26.9 30.1 36.0 35.3VRE 382 0.0 0.0 4.2 6.6 2.9 5.6ESBL - Klebsiella spp. 1,183 46.9 45.8 43.5 46.6 39.5 35.8MDR - P. aeruginosa 762 12.0 14.3 16.0 14.5 17.8 18.7

Latin AmericaNo.

Isolates Tested

% Resistant

1997 1998 1999 2000 2001 2002MRSA 11,156 22.4 27.8 30.7 34.4 38.7 39.1VRE 4,361 13.0 13.6 14.5 15.8 15.7 17.7ESBL - Klebsiella spp. 3,268 5.7 7.9 5.4 5.5 6.3 4.9MDR - P. aeruginosa 1,852 2.5 1.6 2.1 2.0 2.0 3.0

% ResistantNo. Isolates Tested

North America

1997 1998 1999 2000 2001 2002MRSA 5,201 22.1 25.7 30.2 30.8 30.0 28.5VRE 1,922 4.1 43.0 1.6 5.3 1.9 4.4ESBL - Klebsiella spp. 1,941 14.6 25.1 28.7 31.5 20.5 17.3MDR - P. aeruginosa 1,620 5.1 10.1 14.2 9.6 11.7 11.5

EuropeNo.

Isolates Tested

% Resistant

The Global Village and Antimicrobial Resistance

The rapid globalization of food production and trade has increased the potential for international incidents involving food contamination with microbial or chemical hazards

Information on the magnitude of the public health burden due to resistant foodborne pathogens shows that the circumstances are complex and differ by region and country

Can be influenced by a number of variablesHuman and veterinary antimicrobial use practices Process controls at animal slaughter Food storage and distribution systems Availability of clean water Proper cooking and home hygiene methods, among others

Hurry, Sale ends today!!!

Use of Antimicrobials in Food Animal Production and Potential Human Health Implications

Antimicrobial-resistant zoonotic bacterial pathogens are selected, and food is contaminated during slaughter and/or preparation

After consumption of contaminated food, pathogen causes an infection that requires antibiotic treatment and therapy is compromised

Antimicrobial-resistant bacteria non-pathogenic to humans are selected in the animal

After consumption of contaminated food, bacteria transfer resistance determinants to other bacteria in the human gutIncluding both commensal and potential pathogens

Antimicrobials remain as residues in food productsWhich allows for selection of antimicrobial-resistant bacteria after the food has been consumed

A Nationwide Outbreak of Multidrug Resistant S. Typhimurium DT104B Infection in Finland due to

Contaminated Lettuce from Spain, May 2005

Salmonella Typhimurium DT 104B caused an outbreak of 60 microbiologically confirmed cases in May 2005, widely distributed across southern and western Finland

The isolates had identical pulsed field gel electrophoresis (PFGE) and antimicrobial resistance patterns (ACSSuT)

A traceback investigation implicated iceberg lettuce, purchased from a supplier in Spain

Eurosurveillance, 2005, Vol. 10(6)

A Multinational Outbreak of S. Enteritidis Infection in Puerto Vallarta, Mexico

Salmonella Enteritidis caused an outbreak of diarrhealillness at an international scientific conference at a first-class hotel in Puerto Vallarta in 1996

Salmonella Enteritidis phage type 4 was isolated from stool specimens from patients residing in USA, Canada, and the UK

Illness was associated with attending a hotel banquet

Food item associated with illness was chili rellenosIngrediants included shelled eggs and cheese

Shane et al. 2002. Int. J. Infect. Dis. 6:98-102

Salmonella in Imported Fish and Seafood

11,312 imported foods from 1990 to 1998 were examined

Prevalence of SalmonellaOverall 7.2%Seafood 10%Highest 12% (Central Pacific and Africa)

30% (Vietnam)Lowest 1.6% (Europe and North America)

0.7% (Korea)From Heinitz et al. J. Food Prot. 2000. 63:579-592

SalmonellaSalmonella Recovered from Recovered from Imported FoodsImported Foods

FY 2000:FY 2000:187 187 SalmonellaSalmonella representing 82 serotypes representing 82 serotypes recovered from 4,072 samplesrecovered from 4,072 samples

FY 2001FY 2001208 208 SalmonellaSalmonella representing 66 serotypes representing 66 serotypes recovered from 5,000 samplesrecovered from 5,000 samples31% (n = 65) were one of three serotypes31% (n = 65) were one of three serotypes

SS. . WeltevredenWeltevredenSS. Newport. NewportSS. Lexington. Lexington

Zhao et al., 2006. JFP, 69:500-507.

Countries and Regions of Origin of Food Samples Tested for Salmonella

Total: 46 countries, 6 continentsSan SalvadorJordanCosta RicaPhilippinesJapanDenmark

VietnamPanamaIranCroatiaVenezuelaPakistanIndonesiaChinaTurkeyNicaraguaIndiaChileTrinidadMoroccoHong KongCanadaThailandMexicoHondurasCambodiaTaiwanMalaysiaGuatemalaBurmaSyriaMacaoGreeceBrazilSri LankaLebanonGhanaBahamasSpainKoreaEgyptBangladeshSingaporeKampucheaEcuadorAustralia

Imported Food Tested for Salmonella

Seafood: Anchovies, crab, eel, fish, goby, lobster, mackerel, mussels, octopus, oyster, periwinkle, pomfret, scallop, sea bream, shrimp, snail, sole, squid

Fresh produce: cantaloupe, cilantro, coriander, herb leaves, green onions, orange juice, parsley, strawberries

Imported Food Tested for Salmonella

SpicesSpices: Black pepper, chili powder, coriander : Black pepper, chili powder, coriander powder, dried basil, white pepper, celery seed, powder, dried basil, white pepper, celery seed, cumin seeds, herb leaves, dried rosemarycumin seeds, herb leaves, dried rosemary

Dairy productsDairy products: Cheese: Cheese

Exotic meatsExotic meats: Gecko, kangaroo, snake: Gecko, kangaroo, snake

Egg productsEgg products: Duck egg, egg roll: Duck egg, egg roll

Other productsOther products: Candy, mouth rinse, pasta: Candy, mouth rinse, pasta

Top 10 serotypes isolatedTop 10 serotypes isolated

1.1. WeltevredenWeltevreden2.2. LexingtonLexington3.3. NewportNewport4.4. MbandakaMbandaka5.5. ThompsonThompson6.6. EnteritidisEnteritidis7.7. TyphimuriumTyphimurium8.8. AnatumAnatum9.9. InfantisInfantis10.10. ParatyphiParatyphi

1. Weltevreden2. Newport3. Lexington 4. Thompson 5. Senftenberg,

Stanley7. Virchow8. Bareilly

Java10. Braenderup, Derby,

Hvittingfoss, Mbandaka, SchwarzengrundTyphimurium

FY2000 FY2001

Antimicrobial Resistance Profiles of Salmonella

0

10

20

30

40

50

60

70

80

Tet Sul Str Nal Tri Chl

FY2000 (n=15) FY2001 (n=23)

% R

esis

tanc

e

Multidrug Resistant Salmonella

8

11

2.73.4

0

2

4

6

8

10

12

FY 2000 FY 2001

% R

esis

tanc

e

≥ 1 antimicrobial ≥ 3 antimicrobials

Sources of Antimicrobial-Resistant Salmonella

Most seafood products were imported from Southeast AsiaOther food products included:

FY2000:Parsley from Canada, cheese from DenmarkFY2001:Seed spice from Jordan, black pepper from Vietnam, slated yolk from Taiwan, paprika from Spain, parsley from China

An International Outbreak Strain??

Of particular public health significance was the identification of a multidrug resistant (including ciprofloxacin resistance) S. Schwarzengrund isolate recovered from dehydrated chili’s from Thailand

Its PFGE pattern was indistinguishable from that observed among three ciprofloxacin resistant S. Schwarzengrund isolates recovered from human clinical illness in both Denmark and Thailand (personal communication, Dr. Frank Aarestrup and Dr. Rene SjøgrenHendriksen)

This data indicates that global food trade could transmit foodborne pathogens from one country to another

No illness linked to this strain in the U.S.

PFGE profiles of S. Schwarzengrund

Food for Thought

Macovei and Zurek, AEM, 2006, 72:4028-4035

Showed that houseflies in food-handling and -serving facilities carry antibiotic-resistant and potentially virulent enterococci

Antibiotic use/resistance and the consumer

FreshDirect Antibiotic-Free Chicken Penne with Organic Green Beans

Antibiotic freeAir-chilled

Pork Naturally Raised Antibiotic free

Antibiotic free

Evolution of bacteria towards resistance to antimicrobial drugs, including multidrug resistance, is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable

The only realistic means of dealing with this situation is to delay the emergence and subsequent dissemination of resistant bacteria or resistance genes

Therefore, we need to minimize the environmental impact of antibiotics

reduce the extent of exposure, the less likely selection and transfer of resistance traits will occurmultidisciplinary approach is essential if we are to reduce the prevalence of antibiotic resistant bacterial pathogens

Predicting the future?

PUBLIC HEALTH ACTION PLAN TO COMBAT ANTIMICROBIAL RESISTANCE

http://www.cdc.gov/drugresistance/actionplan/

Interagency Task Force created in 1999

A blueprint for specific coordinated federal action to address the emerging threat of antimicrobial resistance

Prevention and ControlProduct DevelopmentResearchSurveillance

Antimicrobial Resistance = Complex Phenomenon

Antimicrobial resistance is a broad-based problem that involves not just patients and doctors/veterinarians in clinical settings, but industry, public health officials, farmers, producers and consumers

The solutions involve a range of federal and state agencies, international governments and organizations, consumer, scientific and professional groups and individuals

Antimicrobial Resistance = Complex Phenomenon

It is most likely impossible to stop antimicrobial resistance from emerging

Resistance is a natural consequence of biological adaptation, which is an inherent factor in the evolution of organisms

Therefore, efforts to tackle antimicrobial resistance should focus primarily on how we can better mediate resistance development and transfer

Additional reading material from ASM press

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http://estore.asm.org/