E. coli / K. pneumoniae

online.web.presentations.com

E. coli / K. pneumoniae

Gram negative

resistance in the

developing world

PROFESSOR PETER M. HAWKEY

School of Immunity and Infection

College of Medical and Dental Sciences

University of Birmingham

Birmingham B15 2TT

Health Protection Agency West Midlands Public

Health Laboratory, Heart of England NHS

Foundation Trust, B5 9SS

peter.hawkey@heartofengland.nhs.uk


CTX-M like β-lactamases

in Kluyvera

K. ascorbata KLUA-1

K. cryocrescens KLUC-1

K. georgiana KLUG-1

Poirel, et al, AAC, 46, 4038


Genetic environment of bla KLUA-1 gene encoding the β-lactamase

produced by K. ascorbata strain CIP 82.95T.

Humeniuk, C., et al, 2002, AAC, 46:3045-9


CTX-M-1

Group

CTX-M-2

Group

CTX-M-8/25/26

Group

CTX-M-9

Group


The CTX-M pandemic, how did it

all start . . .

1989, Paris, Institut Gustave Roussy

Cancer patient isolate of E. coli

Resistant to cefotaxime, ceftazidime; sensitive

to cefoxitin

Transferable 85 kb plasmid

Called MEN-1

Bernard, et al, 1992, JAC, 29:590


The plot thickens . . .

• MEN-1 shown to be identical to CTX-M-1 described in

Germany from an isolate of E.coli 1989 a

• CTX-M-2 described in S. typhimurium from Argentina in

1992 b

• CTX-M-2 then found c

Israel (1992)

Paraguay (1994)

Argentina (1994)

K. pneumoniae

E.coli / P. mirabilis

a

Bauernfeind, et al, 1992, Infection, 18:294

b

Bauernfeind et al, 1992, Infection, 20:158

c

Bauernfeind, et al, 1996, AAC, 40: 509


Some early reports of non-CTX-M ESBLs from Asia

1988 K. pneumonaie China SHV-2

1994 E. gergoviae (1) China (Beijing) SHV-2

1996 K. pneumoniae Korea SHV-12

1997 K. pneumoniae Taiwan SHV-5

1998 E. coli/ Enterobacter China (Guangzhou) SHV-12/11


Bell, et al, 2002, Diag Micro ID, 42:193

Sentry 1999 Asia, % ESBL phenotype all centres

E.coli

K. pneumoniae

Australia 0.2 5.9

Japan 2.6 12.3

Singapore 5.1 41.5

Taiwan 5.8 12.8

Philippines 9.4 31.5

Hong Kong 14.1 13.8

P.R. China 24.5 30.7


Bell, et al, 2002, Diag Micro ID, 42:193

Sentry 1999 Asia, % ESBL phenotype all centres

E.coli

K. pneumoniae

P.R. China

208 35.1 (37) 60 (5)

209 25.9 (81) 27.6 (29)

210 13.3 (43) 29.3 (41)


β-lactamases of 15 representative ESBL producers from

Guangzhou 1 st Municipal People’s Hospital 1998

No. of strains and species

EC KP EN CIT

__________________________________________________

1 1 1 CTX-M-13

2 CTX-M-13, TEM1B

__________________________________________________

2 CTX-M-14, TEM1B

1 1 1 CTX-M-14, SHV-12

__________________________________________________

2 CTX-M-9, SHV-11, TEM1B

1 1 SHV-12, TEM 1B


E.coli + Klebsiella species

Percentage Susceptibility

94NPRS

99NPRS

100

96

99

89

83

Percent

80

60

78

62

72

59

70

58

45

65

54

61

59

66

55

40

39

20

0

Imi

penem

Cefta

zidime

Cefot

axime

Ceftr

iaxone

Piper

acillin

Pip/

tazobact

Ticar/

Clav

Genta

micin

Cipro

floxacin

New NCCLS ESBL Bpts


Asian Countries with High Prevalence of ESBL phenotype

Year Country % (n) ESBL Reference

1999 Pakistan 35 (200) Zaman, Pak Armed Forces Med

J, 1999

1999 China, Japan, Taiwan,

Singapore, Philippine

>20 (2193) Bell, Diagn Microbiol Infect

Dis, 2002

1999 Hong Kong 11-13 (1174) Ho, APMIS, 2000

2002 India 68 (678) Mathur, Ind J Med Res, 2002

2002 Pakistan 48 (400) Shah, New Microbiol, 2002

2002 Pakistan 40 (2840) Jabeen, J Pak Med Assoc, 2005


Aligarh

Varanasi

Hubli


Bacterial Isolates

• Aligarh, N India, July – August 2005

– 1857 samples

– 143 E.coli or K. pneumoniae

– 74 3GC R (51.7%)

• 4 week stored samples 2003-2004 (n=47)

• 19 isolates (10 E.coli, 9 K. pneumoniae) from

Hubli and Varanasi


Characterisation of bla CTX-M in India

130 isolates of E. coli and K. pneumoniae

selected as resistant to 3GCs

95/130 (73%) carried bla CTX-M

All PCR positive were bla CTX-M-15


Community acquired UTI at JNMC Hospital, Aligarh, India

August 2004-July 2005

920 MSU tested in outpatient clinics

10.8% gave significant growth, 100 significant isolates

Resistance %

n ESBL COT NFX GEN AMK

E. coli 61 34% 76 69 64 51

K. pneumoniae 22 22% 53 47 53 35


Proportions and country distributions of CTX-M ESBL genotypes

a

Israel

c

b

Faecal isolates

a Lebanon, b Israel, c Kuwait

CTX-M-1

CTX-M-2

CTX-M-3

CTX-M-9

CTX-M-14

CTX-M-15

Others


• China is dominated by bla CTX-M

genotypes 14, 9 & 3

• Only 4/399 genotyped isolates from

China wide survey bla CTX-M15 *

*Yu et al. J. Infect 2007, 54: 53-7


Prevalence & genotype of bla CTX-M

from Hunan Province 2004/5

bla CTX-M genotype

Species ESBL/Total 3 15 14 9

E. coli 50/160 6 6 35 1

K. pneumoniae 47/110 8 12 13 1

E. cloacae 31/98 10 2 3 3

Citro. freundii 7/17 5 0 0 0

Liu et al 2009 J.A.C. March 18 th epub.


Faecal samples from 20 healthy

children in Kagnoube aged 1-11

years

• Remote village of 60 people only

accessible in dry season

• Shared water pit, no river nearby

• No Western drugs given to children.

Ruppe et al. AAC (2009) 53:3135-7


Kagnoube

Senegal


• 5 random E. coli selected from each

of the 20 faecal samples cultured on

Drigalski agar – all no ESBL’s

• 2 children had 1-4 isolates on agar

ChromID ESBL plates

• Both clonal and CTX-M-15

Ruppe et al. AAC (2009) 53:3135-7


Tunisia

Egypt

Senegal

Mali

South Africa Johannesburg

CTX-M-1

CTX-M-2

CTX-M-3

CTX-M-9

CTX-M-14

CTX-M-15

Others

Hawkey & Jones JAC 2009 64 Supplement 1i3-10


Schematic of the MDR region of pC15-1a

and MDR region of Senegalese clone

(strains KA12 and KA20)

Ruppe et al. AAC (2009) 53:3135-7


CARBAPENEM ANTIBIOTICS...


Global Distribution of VIM-2

*

*

* *

* *

***

*

* *

*

*

*


Distribution of KPC in 2009

Endemic KPC

Sporadic cases of KPC


New Delhi Metallo β-lactamase (NDM)

New class of B1 metallo β-lactamases, 32%

related to NM1/2

• Swedish patient hospitalised in India,

diabetes/strokes. On return to Europe NDM

+ve klebsiella from urine isolated Jan 2008

(180kb plasmid)

No other isolate but E. coli NDM (140 kb

plasmid) +ve found in faecal flora

Yong etal. AAC 2009 53: 5046-54


NDM positive isolates from Sir Ganga Ram

Hospital Delhi

• 9 patients (8/9 hospital inpatients)

• 2 E. coli. 7 Klebsiella

• 4 UTI, 3 cholecystitis, 1 intra-abdominal, 1 VAP

ALL isolates resistant to: ceftazidime, pip-tazobactam,

meropenem, gentamicin, ciprofloxacin

Number of isolates

Sensitive to:

2/9 amikacin

1/9 nitrofurantoin

5/9 tigecycline

9/9 colistin

Antimicrobial Research Group, Birmingham


Cross-sectional study of ESBL carriage by elderly people in

community in Shenyang, China, no collection date.

•19/270 (7%) residents ESBL producing E. coli

•Used EMB with 1μg/ml cefotaxime

•CTX-M-14(11) CTX-M-22/79(6) CTX-M-24(1)

Tian et al. C J Microbiology 54:781-5 (2008)


July 1966 Mao Tse Tung swims the Yangtse at Wuhan

drinks the water and launches the cultural revolution


Microbiology of water from Yangtze at Chonquing,China

thermotolerant coliforms selected on MacConkeys agar

2007-9

319/1914(17%) Enterobacteriacae were ESBL

211/319 carried CTX-M

181/319 carried TEM

88/319 carried SHV

Chen et al Environmental Pollution 2010 epub


Global ESBL Trends

Per Region


Estimated world populations by July 2006

China 1,313,973,713

India 1,095,351,995

World 6,525,170,264


58/242 returning travellers with diarrhoea carried ESBL

producing bacteria.

2/63 (3%) in Europe 50/138(36%) outside Europe

Country

Proportion (%) ESBL E. coli

India 11/14 (79%)

Egypt 19/38 (50%)

Middle East 4/10 (40%)

SE Asia (incl Australia) 5/13 (38%)

Tham et al. 2010 Scand J Infect Dis 42:275-80


Isolates were only identified to group genotype

e.g., group 1, 2, 8, 9 & 25

90% +ve for bla CTX-M

India only gp1

Egypt & Thailand gp1 & 9

China only gp9

Tham et al. 2010 Scand J Infect Dis 42:275-80


FOOD FOR THOUGHT!

• Hong Kong – faeces from pigs, cattle, chickens,

pigeons, geese and ducks sampled (734 samples)

• ESBL phenotype found in:

6 (2%) pigs; 3 (3.1%) cattle; and 1 (3%) pigeons

• ALL bla CTX-M +ve (genotypes 3, 13 and 14)

14 and 3 are the dominant CTX-M ESBLs in

China

Duan, et al, 2006, Microb Drug Resistance, 12: 145-8


CTX-M producing E. coli isolated from chicken meat sole in U.K.

by Country of origin

Origin

Total positive/

Total tested

CTX-M enzyme present

CTX-M-1 CTX-M-2 CTX-M-8 CTX-M-14

British 1/62 1 0 0 0

Irish 0/3 0 0 0 0

Brazil 5/10 0 5 0 0

Brazil/Poland/France 3/4 0 3 0 0

Poland 0/4 0 0 0 0

Netherlands 2/2 0 2 0 0

Spain / France /

Denmark / Germany

0/4 0 0 0 0

Unknown 6/40 0 1 1 4

TOTAL 17/129 1 11 1 4

Warren et al JAC 208 61:504-8


Flow of antibiotic resistance genes in

E. coli in the biosphere

Xenobiotics

e.g. QACs

SOIL

FARM

ANIMALS

Veterinary

Antibiotics

WATER

FOOD

SEWAGE

HUMANS

GUT/FLORA

Clinical

Antibiotics


Li Xu

Vicki Ensor

Jian hui Xiong

mmm

Thomas Ling

Mohammed Shahid

Craig Munday


E. coli n=953 (% resistant)

50

50.6

40

39.4

Percent

30

20

14.4

17.3

29.1

10

0

Ertapenem

0 0

Imipenem

Cefotaxime

Ceftazidime

8

7.1

4.6

2.7

Cefepime

Cefoperazone

Cefoperzone/sul

Amoxycillin/cla

Piperacillin/taz

Ciprofloxacin

Amikacin

2.4

Gentamicin


Antibacterial resistance rates of genetically diverse cephalosporinresistant

E.coli from 3 geographically distinct centres in India

No and % resistant

Ensor, V.M., et al, 2006, J Antimicrob Chemother, 58:1260-3


Study Sites

Centres (Sites)

BJ (3)

SH (3)

ZJ (5)

WH (2)

HN (4)

7 Centres

( 23 Institutions/laboratories)

GZ (5)

HK (1)


2,099 isolates

KLEB

PROT

ESC

PAER

ACIN

OTH

ECOL

Enterobacteriaceae

n=1,616

Ling T. 2004. 44 th ICAAC, Washington DC.


Tande JAC 2010 35:859-65

Adopted children from State orphanage in

Bamako, Mali, Africa coming to France

Positive for ESBL E. coli

90% bla CTX-M +ve : all CTX-M-15

10% SHV-12


ANTRES project

Antibiotic resistance in Peru and Bolivia

• Large scale survey of faecal E. coli in pre-school

healthy children

• 1 st January 2002, reported 2005

• ESBL rate 0.1%

1.7% due to CTX-M spread

Pallecchi, et al, 2007, AAC, 51: 2720


Geographic distribution of CTX-M E.coli, 2005 ANTARES study

Pallecchi, et al, 2007, AAC, 51: 2720


CTX-M

group

Type No Antibiotic resistance

co-transferred

Plasmid Inc

group

CTX-M-2 CTX-M-2 8 GEN A/C; I1

4 GEN TET SXT F VII

2 GEN TET A/C

1 TET A/C

1 GEN SXT -

CTX-M-56 2 GEN A/C

CTX-M-9 CTX-M-14 8 NONE I1

CTX-M-24 2 NONE I1

CTX-M-1 CTX-M-15 6 NONE

1 TET CIP* FII

1 TET CIP* GEN FII

* aac (6')–Ib-cr

Pallecchi, L., et al, 2007, AAC, 51: 2720-5


Proportion of 3 rd generation cephalosporins

resistant to E. coli isolates, EARSS data

2001

2006


Laupland et al. J Infection 2008 Dec;57(6):441-8.


Some early reports of CTX-M ESBLs from Asia

1993 E. coli Japan Toho-1

1995 E. coli Japan Toho-2

1995 E. coli / Shigella / K. pneumoniae Korea CTX-M-14

1997 E. coli Japan CTX-M-2

1998 E. coli / K. pneumoniae / Enterobacter China

(Guangzhou)

CTX-M-14/13/9*

1998 E. cloacae / K. pneumoniae/ Serratia Japan CTX-M-3

1999 E. coli / K. pneumoniae/ E. aerogenes India CTX-M-15

* Chanawong, et al, 2002, AAC, 46: 630


Asian Countries with High Prevalence of ESBL phenotype

Year Country % (n) ESBL Reference

1999 Pakistan 35 (200) Zaman, Pak Armed Forces Med

J, 1999

1999 China, Japan, Taiwan,

Singapore, Philippine

>20 (2193) Bell, Diagn Microbiol Infect

Dis, 2002

1999 Hong Kong 11-13 (1174) Ho, APMIS, 2000

2002 India 68 (678) Mathur, Ind J Med Res, 2002

2002 Pakistan 48 (400) Shah, New Microbiol, 2002

2002 Pakistan 40 (2840) Jabeen, J Pak Med Assoc, 2005

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