Transfer of resistant bacteria from animals to humans – relation to

antibiotic use as growth promoters and therapeutics

Niels Frimodt-MøllerProfessor, MD, DMSc.

Dept. for Microbiological Surveillance and ResearchStatens Serum Institut

CopenhagenDenmark

Antibiotic resistance: Clinical consequence

Odds Ratio (95% CI) for mortality

S.aureus: MR vs MS Cosgrove et al. CID 2003;36:53-59

1,93 (1,54 – 2,42)*

E. coli: FQ-R vs FQ-S

Lautenbach et al. CID 2005;41:923-9

4,41 (1,03 – 18,81)*

Enterococcus: VR vs VS DiazGranados et al. CID 2005;41:327-33

2,52 (1,9 - 3,4)*

S.pneumoniae: PenR vs PenS Tleyjeh et al. CID 2006;42:778-97

1,29 (1,04 – 1,59)*

* P < 0.05

Vancomycin resistant E. faecium

- the growth promoter case

Enterococcus faecium: Vancomycin resistant (VRE) ~ vanA gene, located on transposon, transferable via plasmid

1988: Clinical isolates of VRE found in human infections in France and UK Jordens JZ et al. J. Antimicrob. Chemother.34:515–528.; Uttley AHC et al. 1988. Lancet I, 57– 58;

Leclercq R N Engl J Med 1988; 319: 157–161.

Not related to Vancomycin consumption in humans, but to Avoparcin(Vancomycin analogue) use as growth promoter

Bates J et al.J. Antimicrob.Chemother. 1994, 34:507–516.

1995: Denmark proves direct connection between Avoparcin use and VRE in poultry and pigs – and bans Avoparcin

Aarestrup, F. M. 1995. Microb.Drug Resist. 1:255–257.

2000: EU ban on all growth promoters

Ultimate risk: Transfer of vanA to Staphylococcus aureus ? Noble, C. J. 1978. J. Clin. Pathol. 31:1182–1186.

Enterococcus faecium: Vancomycin resistant (VRE) ~ vanA gene, located on transposon, transferable via plasmid

1988: Clinical isolates of VRE found in human infections in France and UK Jordens JZ et al. J. Antimicrob. Chemother.34:515–528.; Uttley AHC et al. 1988. Lancet I, 57– 58;

Leclercq R N Engl J Med 1988; 319: 157–161.

Not related to Vancomycin consumption in humansSuspicion on Avoparcin (Vancomycin analogue) use as growth promoter

Bates J et al.J. Antimicrob.Chemother. 1994, 34:507–516.

1995: Denmark proves direct connection between Avoparcin use and VRE in poultry and pigs – and bans Avoparcin

Aarestrup, F. M. 1995. Microb.Drug Resist. 1:255–257.

2000: EU ban on all growth promoters

Ultimate risk: Transfer of vanA to Staphylococcus aureus ? Noble, C. J. 1978. J. Clin. Pathol. 31:1182–1186.

Isolation from a patient of a vancomycin resistant S. aureus containing the vanA element from E. faecalis present in same wound Flannagan et al. AAC 2003; 47:3954–9.

Growth promoters select for resistance in animals and transfer of resistance (or resistant bacteria) from food production animal to humans ? e.g. vancomycin resistant E. faecium (VRE)

Proof of:

Resistant bacteria (VRE) in animals in farm

VRE in animals at slaughter

VRE in meat (products) from animals

VRE in gut (feces) of humans eating meat

and not found in gut (feces) of vegetarians

VRE in gut (feces) of patients

VRE in infections (as in gut)

Experimental uptake and colonization in gut (feces) of VRE

Experimental transfer of resistance genes in gut (feces) of VRE

Disappearance of VRE with reduction of antibiotic selection

Correlation between use of Avoparcin as growth promoter and prevalence of Vancomycin-Resistant E. faecium (VRE)

Poultry farms No. of flocks investigated

No. of flocks with VRE

+ avoparcin in

feed 40 32

- avoparcin in

feed 32 2

Aarestrup, F. M. 1995. Occurrence of glycopeptide resistance among E.faecium isolates from conventional and ecological poultry farms. Microb.Drug Resist. 1:255–257.

Transfer of VRE from animal to humans: Scientific evidence

Same type VRE in poultry and farmer

Simonsen et al. Microb Drug Resist. 1998; 4: 313-8.

Same VRE in poultry before and after slaughterAarestrup et al. APMIS 1998; 106:606–22

VRE in food. Wegener et al. Int J Food Microbiol 1997; 35:57–66. Robredo Int J Food Microbiol. 2000; 54: 197-204.

VRE carriers in countries, where avoparcin used, but not elseIeven [abstract LB-8, 41st ICAAC, 2001. Klare et al. Microb Drug Resist. 1999; 5: 45-52. Klare et al. Microb Drug Resist. 1995;1: 265-72.

Same type VRE in pigs and patients Jensen et al. AAC 1999; 43:724–5; Hammerum et al. JAC 2004; 53:547–9.

Results of ban of growth promoters Avoparcin and Virginiamycin in Denmark

Fecal carrier rates of Vancomycin Resistant E. faecium (VRE) in non-hospitalised humans

0

5

10

15

20

25

30

1994 1996 1996 1997 1997 1999 2003

12/100 11/40 6/100 13/400 1/670 3/169 2/6023% pos with VRE

Ban of Avoparcin

Van den Bogard et al., JAC 2000, 46: 146Van den Auwera et al. JID 1996, 173: Klare et al. Microb Drug Resist. 1999;5:45-52. Gambarotto et al. J Clin Microbiol. 2000; 38: 620–624. Torell et al. J Clin Microbiol. 1999; 37: 3509–3513 Kolar et al.J Med Microbiol. 2005; 54: 965-7.

.

SF

D

NL

D

CzD

Significant decrease of VRE infections and colonization rates in patients at hospital admission after AGP ban

0

2

4

6

8

10

12

14

1996 2001

Colonization at admission

0

0,5

1

1,5

2

2,5

3

3,5

4

1998 2001 2002

Infections in hospitals

W. Witte, personal comm. M. Leven et.al. ICAAC 2001

Germany Belgium

N=335 N=353

% v

anA

% v

anA

Growth promoters select for resistance in animals and transfer of resistance (or resistant bacteria) from food production animal to humans ? e.g. vancomycin resistant E. faecium (VRE)

Proof of:

Resistant bacteria (VRE) in animals in farm

VRE in animals at slaughter

VRE in meat (products) from animals

VRE in gut (feces) of humans eating meat

and not found in gut (feces) of vegetarians

VRE in gut (feces) of patients

VRE in infections (as in gut)

Experimental uptake and colonization in gut (feces) of VRE

Experimental transfer of resistance genes in gut (feces) of VRE

Disappearance of VRE with reduction of antibiotic selection

Use of Streptogramin Growth Promotersin Poultry and Isolation of Streptogramin-ResistantEnterococcus faecium from HumansKieke et al. The Journal of Infectious Diseases 2006; 194:1200–8

Minnesota, Wiscosin, USA

Campylobacter

Campylobacter infection: Clinical consequences

• 121 cases with extra-digestive manifestations admitted to French hospitals were reviewed: 88% had bacteraemia; 15% died (Tchamgoue et.al., ICAAC 2001, abstract no. L-770)

Campylobacter, erythromycin-resistance and relative mortality

• 4,7 times higher risk of death when infected with erythromycin-resistant Campylobacter

• There is a trend of decreasing erythromycin resistance in Danish Campylobacter spp. after ban of growth promoters

• In 2001, there were 104 fewer Campylobacter cases in Denmark, with 3,5 fewer deaths

Helms et al. JID 2005; Molbak et al. 2002

Macrolide use and - resistance in Campylobacter coli from pigs

0

10

20

30

40

50

60

70

80

Per

cen

t re

sist

ance

0

5

10

15

20

25

30

35

40

45

50

Co

nsu

mp

tio

n (

mg

/Kg

)

C. coli Macrolide use

Salmonella

Antibiotic resistant Salmonella: Clinical importance

• Ciprofloxacin-R Salm. had a significantly longer fever defervescence time (7.7 vs 4.7 days, p<0.001) and hospital stay (12.1 vs 8.2 days, p<0.001), and higher rates of complications (55.5% vs 24.0%, p=0.014) and mortality than cipro-S Salmonella Walia et al. Ann Trop Paediatr. 2005; 25:161-74

• Antibiotic resistant Salmonella Typhimurium was associated with a 3.15-fold (95% confidence interval, 1.39-7.10-fold) higher risk of invasive illness or death within 90 days of infection, compared with that observed for infection with pansusceptible strains.

Helms et al. J Infect Dis. 2004; 190: 1652-4

Salmonella: Antibiotic resistance associated with antibiotic use ?

Salmonella as a primary human pathogen is seldom carried by humans (e.g. chronic carriers occur) and therefore not subjected to selection by antibiotic use in humans

In contrast, Salmonella is carried by production-animals (i.e. not causing infection) and therefore present in reservoirs where antibiotic selection during treatment with antibiotics takes place

Therefore, most antibiotic resistance in Salmonella is due to selection by antibiotics used in animals

No. of human Salmonella, Campylobacter and Yersinia cases in Denmark 1980-2009

E. coli

E. coli: Intestinal commensal, causing

diarrhoea or extraintestinal infections such as urinary tract infection (UTI)

Lautenbach et al. CID 2005;41:923-9

Manges et al, NEJM 2001, 345: 1007; Burman et al., Am J Med 2003, 115: 358; Johnson et al. Lancet 2002; 359:2249; Phillips et al. Lancet 1988, 331: 1038; Olesen et al. SJID 1994, 26: 406; Pitout et al. JCM 2005; 43: 2844

• UTI: Annually 6-8 mill. cases in USA, 130-175 mill. cases globally; >80% associated with E.coli; most common source of bloodstream infections ~ 40.000 deaths/y in USA

• Antibiotic resistance in E.coli increases mortality with a factor 2 - 4

• Since 1980´ies several reports of state- or countrywide outbreaks with clones of antibiotic-resistant E. coli causing UTI including pyelonephritis

E. coli: UTIIncreasing evidence of production-animals/food as source:

• Resistance and virulence genes in human E. coli (both found in feces and in UTI) and E. coli in production animals and related food products are highly correlated (exact same DNA-types)

Vincent et al. Emerg Infect Dis 2010; Jakobsen et al., submitted

• Resistance genes, e.g. for sulphonamides, in E. coli from humans and production animals carry the exact same mutations – and different between e.g. poultry and pigs Trobos et.al. Microbiology 2009

• Experimental intake of resistant E. coli in food leads to high level colonization without antibiotic selection.

Trobos et al. JAC, 2009

Conclusion: Transfer of resistance animal > human:

Enterococci, Salmonella, Campylobacter and E. coli:

• Antibiotic resistance in these pathogens when causing infection in humans is associated with a worse outcome, even increased risk of death

• Scientific evidence is amounting that enterococci and E. coli – as is well known for Campylobacter and Salmonella - are spread via the food chain

• The evidence further shows, that the risk for humans includes antibiotic resistance, which is highly correlated to antibiotic use in production-animals

• Ban of growth promoters prevented spread of VRE in humans, reduced resistance in pathogens like Campylobacter, and reduced serious human infections (e.g. macrolide-resistant Campylobacter)

Acknowledgements:

Anette Hammerum

Camilla Lester

Lotte Jakobsen

Margareta Trobos

Frank Aarestrup

DANMAP editorial group

Why was VRE more prevalent in US hospitals than in Europe ?Vancomycin usage in USA vs. Europe

Klare et al. IJFM 2003

EARSS 2008

Staphylococcus aureus (Sa): MRSA epidemiology

Spa types in 2008

1 % of SA bacteraemias

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