Asima ZehraSchool of Public Health and

ZoonosesGADVASU

Antibiotic Resistance from food of animal origin- A debatable

issue

overview

Introduction Situation around the worldDrivers of antibiotic resistanceFood of animal origin as a source of AR bacteria

Examples

IntroductionSince the first use of antibiotics in the 1930s and 1940s, bacteria quickly adapted and developed mechanisms to escape their effectsSince the 1990s, new antibiotic development has fallen sharply while bacterial resistance continues to increaseAntibiotic resistance is responsible for

countless human deaths and billions of dollars in healthcare expenses

Antibiotic Mechanism of Action

Daptomycin

Linezolid

Linezolid

Global Scenario

MEATOnly around 20-30% of antibiotic used for humans

>50% of antibiotics are used for livestock

only in most of the countries

20-30%>50%

Trillions

Antibiotic resistance – a problem in the present and the future

Antibiotic resistance is an increasingly serious public health problem: resistant bacteria have become an everyday concern in hospitals of Europe

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2002 2003 2004 2005 2006 2007 2008

Prop

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n of r

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ant is

olate

s (%

)

Penicillin-non susceptible S. pneumoniae (EU pop.-weighted average)

Erythromycin-resistant S. pneumoniae (EU pop.-weighted average)

Fluoroquinolone-resistant E. coli (EU pop.-weighted average)

Third-gen. cephalosporin-resistant E. coli (EU pop.-weighted average)Trends in antibiotic resistance (invasive infections), 2002-2008. Source: European Antimicrobial Resistance Surveillance System (EARSS), 2009.

Increase in MRSA Prevalence in US Comparison to Other Drug-Resistant Organisms

2002

No data

<1%

1-5%

5-10%

10-25%

25-50%

>50%

Source: European Antimicrobial Resistance Surveillance System (EARSS), 2008.

2007

Wenzel et. al. ICHE 2008;29;1012

MRSA Resistance Rates from Studies in India Vary but

Appear to Increase Over Time

Source: Data from all studies described in the section on MRSA in India, excluding those that did not specify when data was collected.

MRSA (Methicillin-Resistant Staphylococcus aureus) Resistance Rates in India

National Staphylococcal Phage Typing Centre

A study of 7,574 S. aureus strains received between 1992 and 1998 at the National Staphylococcal Phage Typing Centre in New Delhi found that

MRSA climbed from 10 percent in 1992 to 45 percent in 1998 (Mehndiratta et al. 2001). In Europe, S. aureus

resistance to oxacillin ranged from over 50 percent in Romania to less than 1 percent in Norway and Sweden in 2006.

Most Mediterranean countries and the United Kingdom had MRSA rates between 25 and 50 percent, similar to those found in India (Gould 2008).

Susceptibility of S. pneumoniae to Fluoroquinolones in Canada

Relationship of Resistance to Antibiotic Use

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1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998

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15 - 64 y.o> 64 y.o# of Rx/100 persons

Chen et. al., NEJM 1999;341:233-9

Available National Data* on Resistance for Nine Selected Bacteria/Antibacterial Drug

Combinations, 2013

*National data means data obtained from official sources, but not that data necessarily are representative for the population or country as a whole

Neisseria Gonorrhoeae Detection of decreased susceptibility to 3rd generation

cephalosporin and treatment failures up to 2010

Antibiotic Use Leads to Antibiotic Resistance

Outpatient

Inpatient

Agriculture

Environment

Misuse of antibiotics drives antibiotic resistance

Studies prove that misuse of antibiotics may cause patients to become colonised or infected with antibiotic-resistant bacteria, such as meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and highly-resistant Gram-negative bacilli. (Safdar and Maki 2002; Tacconelli et al 2009)

Misuse of antibiotics is also associated with an increased incidence of Clostridium difficile infections.

(Davey P et al 2005; Fowler et al. 2007)

• Antimicrobial administration to food animals is among the important factors contributing to the selection of antimicrobial- resistant bacteria that can be transmitted from animals to humans.

• More than half of all antibiotics produced globally

are used in animals [ECDC].

Cycle of Antibiotic Resistance Acquisition: Bacterial Selection Under increasing

antibiotic selection pressure:1. Bacteria resistant

to a particular drug are selected and replicate

2. Different antibiotics select different bacteria but can select resistant phenotypes to other drugs as well

3. This results in multidrug-resistant (MDR) organisms and increases their total number

Replication

Replication

Selection by Drug X

Selection by Drug YResistance to:Drug X Drug Y Drug Z

Is CHICKEN full of antibiotics to blame for rise in drug

resistance?

A new study by the Centre for has revealed that rampant unregulated use of antibiotics in the poultry industry could be a contributing factor to Indians developing a resistance against antibiotics.And that could be the reason why Indians are falling prey to several ailments that are otherwise curable.

Science and Environment (CSE)

With nearly 40 per cent of the tested samples of chicken being found to be heavy in antibiotics.

"Antibiotics are no more restricted to humans nor limited to treating diseases. The poultry industry uses antibiotics as a growth promoter. Chickens are fed antibiotics so that they gain weight and grow faster," said Sunita Narain, director general, CSE.Seventy samples of chicken in Delhi and NCR were tested to detect the presence of six antibiotics widely used in poultry. These include oxytetracycline, chlortetracycline and doxycycline, enrofloxacin, ciprofloxacin and neomycin, an aminoglycoside.

Residues of nearly five of the six antibiotics were found in the chicken samples.

CSE Recommendations to GovernmentBan use of antibiotics as growth promoters to

prevent diseasesThose antibiotic that are harmful for humans shld not

be allowed in the poultry industryAntibiotic shld not be used

as a feed additive and the govt shld regulate the poultry feed industrySet pollution control

standards for the poultry industryUnlicenced and unlabelled

antibiotics should not be sold in the marketThe govt shld promote

development of alternatives and good farm management

practicesSet standards for antibiotics in chicken

productsSet up a system for

monitoring and surveillance of antibiotic use and AR in human and

animals

??

??

India needs “An implementable antibiotic policy” and NOT “A

perfect policy”

Antibiotic Resistance in animalsResult Reference

Antibiotic-resistance patterns of Salmonella in eggs in South India

7.7% samples positive for Salmonella and all were resistant to ampcillin, neomycin, polymyxin-B and tetracycline

Suresh et al. 2006

Salmonella isolates from horses, donkey and mules

91% resistant to sulamethoxazole, 71% to tetracycline, 68% doxycycline

Singh et al. 2007

Antibiotic resistance among enterococci isolated from horses (and related animals) in North India

80.2% of strains resistant to vancomycin.

Singh 2009These studies highlight the growing threat of antibiotic resistance to both animal and human health in India.

• The same strains of MRSA have been found in livestock and livestock workers in The Netherlands, Italy, Canada and the USA*

[Van Loo I 2009; Soavi L et al 2010]

• In The Netherlands, 94% of a representative sample of chicken retail meat was contaminated with ESBL-producing E. coli isolates, of which 39% were also found in human clinical samples tested in 31 microbiological laboratories** [Overdevest et al 2011]

• Reports of the spread of multidrug resistant Salmonella Schwarzengrund from chickens to humans in Thailand and from imported Thai food products to humans in Denmark and the USA. [Aarestrup et al 2007]

Salmonella• Multidrug-resistant Salmonella

typhimurium definitive type 104 (DT 104) initially emerged in cattle in 1988 in England and Wales

• Subsequently found in meat and meat products from other domestic animals, as well as unpasteurized milk from other locations. (Threlfall EJ et al, 1997)

The percent positive samples for Salmonella included human stool (20.5%) and poultry cloacal swabs (14.7%).

Three Salmonella serovars were common between poultry and humans, resulting in same pattern of decreasing frequency; these serovars were S. Typhimurium, S. Enteritidis, and S. Paratyphi B.

[Murugkar HV et al 2005]

Campylobacter jejuni

• The approval of fluoroquinolones for veterinary use in Europe led to the emergence of antibiotic resistant Campylobacter jejuni in human and chicken populations.(ECDC)

DNA sequencing revealed a high degree of variation in DNA gyrase, the target of fluoroquinolones; thus, even without any selective pressure, these bacteria showed the same alterations in the target sequence as those isolated from clinical and laboratory environments.

• Campylobacter antibiotic resistance was 40% for nalidixic acid, 23.3% for ciprofloxacin, 50% for tetracyclin and 20% for streptomycin.

(Vaishnavi C. 2015)

E. coli O157:H7• A longitudinal study of E. coli O157:H7

dissemination related the therapeutic and subtherapeutic (in feed) use of antibiotics and the occurrence of antibiotic-resistant isolates on Wisconsin farms.

(Shere JA et al 1998) • Over a 14-month period, subtherapeutic use

of antibiotics* and therapeutic use of sulfamethazine to treat diarrhea correlated well with the emergence of antibiotic-resistant E. coli O157:H7 on the farms.

Antimicrobial susceptibility profile of 63 STEC isolates from 19 human faecal samples, 40 cattle samples and 4 food samples in Kolkata were assessed.

The strains were resistant to ampicillin (25.4%), tetracycline (23.8%), streptomycin (14.3%), cephalothin (1.1%), cotrimoxazole (9.5%), nalidixic acid (6.4%) and neomycin (3.2%). 14 strains showed resistance to multiple antibiotics but no common pattern was observed among the strains

[Khan A. et al 2002].

• Although evidence tying sub-therapeutic antibiotic use in livestock and AR has been largely circumstantial, a 2011 experiment offered direct evidence.

• Highly controlled trial took piglets from the same litter and raised them in two groups under the same conditions, except that one group was given low doses of antibiotics in the feed.

(Looft Torey et al. 2012)• After only two weeks, the treated piglets developed

significantly higher levels of AR Escherichia coli. • The AR E. coli in the treated piglets carried a higher

variety of AR genes, including some that conferred resistance to drugs not used in the study

(Ibid)

• A study of poultry workers found the presence of a strain of E. coli resistant to gentamicin, an antibiotic commonly used in chickens, to be 32 times higher in the workers compared to other members of the community.

• Half of the poultry workers carried the AR strain, compared to 3 percent of the neighboring population (Price LB et al. 2007)

• AR bacteria have sickened farm family members too.

MRSA• MRSA was once considered only endemic to

hospitals, but one strain of MRSA, ST398, has been found in food production animals, in people who work with those animals and in retail meat. (Kluytmans 2010)

• Researchers have found strong evidence that this strain of MRSA originated in humans, migrated to pigs where it acquired antibiotic resistance, and now is infecting humans again. ( Price et al 2012)

• Studies of MRSA have found mixed results

vancomycin• Molecular genetic analysis of vancomycin

resistant isolates from the feces of pigs and poultry in Denmark and of the transposon Tn1546, isolated from humans, suggests that there has been transmission among humans, farm animals and household pets (McDonald LC et al 1997)

Conclusion• Inappropriate and excessive use of

antibiotics is a major factor contributing to emerging antibiotic resistance

• Determinants of resistance are selected for by antibiotic use

• Multiple factors are responsible for bacteria to become resistant to antibiotics

• It is clear, however, that raising livestock without antibiotics does not add to the reservoir of resistance.

• Antibiotic resistance continues to emerge as a serious threat to public health

References• Levy SB. The antibiotic paradox. How miracle drugs are destroying the

miracle. New York: Plenum Press; 1992.• Dewey CE, Cox BD, Straw BE, Budh EJ, Hurd HS. Association between

offlabel feed additives and farm size, veterinary consultant use and animal age. Prev Vet Med 1997;31:133-46.

• Tenover FC, McGowan JE Jr. Reasons for the emergence of antibiotic resistance. Am J Med Sci 1996;311:9-16.

• Gillespie JR. Modern livestock and poultry production. Albany (NY): Delmar Publishing; 1997.

• Feinmen SE. Antibiotics in animal feed: drug resistance revisited. Am Soc Microbiol News 1998;64:24-30.

• Chadwick DJ, Goode J, organizers. Antibiotic resistance: origins, evolution, selection, and spread. Ciba Foundation Symposium 207. New York: John Wiley and Sons; 1997. Chap 1–3, 5, 8, 9.

• Threlfall EJ, Ward LR, Skinner JA, Rowe B. Increase in multiple antibiotic resistance in nontyphoidal salmonellas from humans in England and Wales; a comparison of data for 1994 and 1996. Microb Drug Resist 1997;3:263-6.

• Lee LA, Puhr ND, Maloney FK, Bean NH, Taupe RV. Increase in antimicrobial- resistant Salmonella infections in the United States, 1989-1990. J Infect Dis 1994;170:128-34.

• Endtz HP. Quinolone resistance in campylobacter isolated from man and poultry following the introduction of fluoroquinolones in veterinary medicine. J Antimicrob Chemother 1991;27:199-208.

• Waters B, Davies J. Amino acid varieties in the gyrA subunit of bacteria potentially associated with natural resistance to fluoroquinolone antibiotics. Antimicrob Agents Chemother 1997;41:2766-9.

• Shere JA, Bartlett KJ, Kaspar CW. Longitudinal study of Escherichia coli O157:H7 dissemination on four dairy farms in Wisconsin. Appl Environ Microbiol 1998;64:1390-9.

References Cont.• McDonald LC, Kuehnert MJ, Tenover FC, Jarvis WR. Vancomycin-resistant

enterococci outside the health care setting: prevalence, sources, and public health implications. Emerg Infect Dis 1997;3:311-7.

• Howarth E, Poulter D. Vancomycin resistance: time to ban avoparcin [letter]. Lancet 1996;347:1047.

• European Centre for Disease Prevention and Control (ECDC), European Food Safety Authority (EFSA), European Medicines Agency (EMEA) and the European Commission’s Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR): Joint Opinion on antimicrobial resistance (AMR) focused on zoonotic infections. EFSA J 2009, 7:1372 [http://www.efsa.europa.eu/it/efsajournal/doc/1372.pdf].

• Price Lance et al. 2012. Staphylococcus aureus CC398: Host Adaptation and Emergence of Methicillin Resistance in Livestock.” mBio. 3(1): 1

• Khanna T et al 2008. “MRSA colonizatio in pigs and pig farmers”. Veterinary Microbiology. 128: 298

• Price LB et al. 2007. “Elevated risk of carrying gentamicin-resistant Escherichia coli aming U.S poultry workers”. Environmental Health Perspectives. 115: 1738-40

• Chetana Vaishnavi, Meenakshi Singh, Jarnail Singh Thakur, Babu Ram Thapa. 2015. Low Prevalence of Campylobacteriosis in the Northern Region of India. Advances in Microbiology, 2015, 5, 155-165.

• Murugkar HV, Rahman H, Kumar A, Bhattacharyya D (2005) Isolation, phage typing and antibiogram of Salmonella from man and animals in northeastern India. Indian J Med Res 122: 237-242.

• Rajagopal R, Mini M (2013) Outbreaks of salmonellosis in three different poultry farms of Kerala, India. Asian Pac J Trop Biomed 3: 496-500.

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