/dr_timothy_walsh

NDM-­‐1 and other emerging pathogens: A microcosm of the resistance problem

Timothy R. R.Walsh Walsh Timothy

Andrei Dmitrievich Sakharov (Андре́й Дми́триевич Са́харов) (May 21, 1921 – December 14, 1989) ( Nobel Peace Prize in 1975)

“The second basic thesis is that intellectual freedom is essential to human society — freedom to obtain and distribute information, freedom for open-minded and unfearing debate and freedom from pressure by officialdom and prejudices. Such a trinity of freedom of thought is the only guarantee against an infection of people by mass myths, which, in the hands of treacherous hypocrites and demagogues, can be transformed into bloody dictatorship. Freedom of thought is the only guarantee of the feasibility of a scientific democratic approach to politics, economics and culture” (Reflections on Progress, Peaceful Coexistence, and Intellectual Freedom, July 22, 1968.

Strain Organism

Data from India – 1998 to 1999

Walsh et al., 2007. J Antimicrob Chemother. 59(4): 799-800.

#1 #2 #3 #4 #5 #6 #9 #10 #11 #12 #13 #14 #15 #16 #17 #18 #19 #20 #21 #22 #23 #24 #25 #26 #27 #28 #29 #30 #31 #32 #33 #34 #35 #36 #37 #38 #39 #40 #41 #42 #43 #44 #45 #49 #50 #60

E.coli A4/7 E.coli A4/8 E.coli A4/11 Klebs spp A5/3 Klebs spp A5/4 Klebs spp A5/7 E.coli B4/6 E.coli B4/12 Klebs spp B5/11 E.coli B5/14 Klebs spp B5/16 Klebs spp B6/1 Klebs spp B6/4 Klebs spp B6/5 Klebs spp B6/10 E.coli C4/3 E.coli C4/12 K.pneumoniae C5/5 K.pneumoniae C5/7 K.pneumoniae C5/8 E.coli D4/11 E.coli D4/12 K.pneumoniae D5/4 K.pneumoniae D5/12 E.coli E4/1 E.coli E4/4 E.coli E4/6 Klebsiella E5/14 Klebsiella E5/17 Klebsiella E5/19 Enterobacter F2/6 Enterobacter F2/9 E.coli F4/3 E.coli F5/10 Klebsiella F5/6 Klebsiella F5/10 Klebsiella F5/11 E.coli G4/10 E.coli G4/12 E.coli G4/13 Klebsiella G5/2 Klebsiella G5/6 Klebsiella G5/11 E.coli H4/5 E.coli H4/8 E.coli I4/3

ESBL + + + + + + + + + ? ? + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

TEM SHV

CTXM1 CMY2 Oxa1type

TEM-1 TEM-1 TEM-1 TEM-1 TEM-1 TEM-1

CTXM-15

ND TEM-1 TEM-1 TEM-1

ND TEM-1 TEM-1 TEM-1 TEM-1 TEM-1 TEM-1 TEM-1 TEM-1 TEM-1

ND TEM-1 TEM-1

ND TEM-1 TEM-1

NEW TEM-1 TEM-1 TEM-1 TEM-1 TEM-1

ND TEM-1 TEM-1 TEM-1 TEM-1 TEM-1

ND TEM-1 TEM-1 TEM-1 TEM-1 TEM-1 TEM-1 TEM-1

SHV-1 SHV-1 SHV-1 SHV-1 SHV-1 SHV-1 ND ND SHV-1 SHV-1 SHV-1 SHV-1 SHV-1 ND ND SHV-1 SHV-1 SHV-1 SHV-1 SHV-1 -

CTXM-15

CTXM-15 CTXM-15 CTXM-15 CTXM-15 CTXM-15

CTXM-15 -

CTXM-15 -

CTXM-15 CTXM-15 CTXM-15 CTXM-15

CTXM-15 ND CTXM-15

CTXM-15 CTXM-15 CTXM-15 CTXM-15 CTXM-15 CTXM-15

CTXM-15 ND

CTXM-15 CTXM-15 -

CTXM-15 CTXM-15 CTXM-15 CTXM-15

CTXM-15 CTXM-15 CTXM-15 CTXM-15 CTXM-15

CMY7 CMY4 CMY4 ND CMY6 -

OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 ND OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1

Oxa2type + + + +s + +? + + +s + + ND +s + + -

Canton and Coque, 2006

Medical tourism Naming of NDM-1

Chronological Events after first publication • • • • • • • • • •

August 12th –release of 1st paper August 12 th-20th -Harassment of Indian colleagues August approx. 24th –Indian researches told not to work on NDM September -Indian scientists told it is illegal to send isolates out of India October –Meeting in New Delhi to formalise status on NDM Meeting in New Delhi to formalise status on NDM-1 and lay down rules October/November –Indian Govt sets up task force to tackle AR March 2011 –Indian strategy to tackle AR published April 7th 2011 –Second LID paper published April 8 -9th –Indian Govt rebuttal April 15th –Indian Govt announced grants to work on NDM Indian Govt announced grants to work on NDM

Medical tourism Naming of NDM-1

Location of NDM-1 – May 2011 The new CTX-M?

Richard Horton, Pam Das The Lancet, London NW1 7BY, UK. January 12, 2011

Naming of Resistance genes • Suggested by the researcher and approved by the gate keepers • History of NDM-1 prior to the Lancet • Bacteria have been named by Indian researchers after the capital city • Examples of names: VIM-1: Verona imipenemase SPM-1: Sao Paulo metallo-β-lactamase GIM-1: German imipenemase DIM-1: Dutch imipenemase AIM-1: Adelaide imipenemase

What s the problem?

MRSA Rates

2002

2009

Table 1a: Quarterly counts of MRSA bacteraemia Table 1a: Quarterly counts of MRSA bacteraemia (April 2007 - March 2011) Data are as extracted from the HCAI Data Capture System on April 21st 2011.

These tables contain data which were submitted by the final submission deadline. Data are provisional. Late submissions of data corrections wil be incorporated in future publications.

Italic type indicates that one or more cases refer to identified cases that have been dually reported or accepted as extenuating circumstances (Please see Supplementary Table for further details) Alphabetical order

Trust Trust code type HPA Region

Name of NHS Trust Total

MRSA bacteraemia reports July to October to July to October to July to October to July to October to April to June September December January to April to June September December January to April to June September December January to April to June September December January to 2007 2007 2007 March 2008 2008 2008 2008 March 2009 2009 2009 2009 March 2010 2010 2010 2010 March 2011 Name of NHS Trust 1,306

1,083

1,092

970

839

724

678

694

510

462

443

483

421

395

331

334 Total

REM RCF RBS RTK RF4

FT FT FT FT --

North West Yorkshire & the Humber North West South East London

Aintree University Hospitals Airedale Alder Hey Children's Ashford & St Peter's Hospitals Barking, Havering & Redbridge Hospitals

14 3 1 4 9

3 4 0 2 11

9 2 1 3 8

7 3 0 6 12

8 1 1 4 10

9 4 0 6 8

5 3 2 6 12

6 4 4 4 8

6 2 2 1 9

7 1 0 5 8

0 2 2 2 8

5 2 1 1 14

4 1 1 7 8

1 2 0 1 4

3 2 1 0 10

0 0 0 0 8

Aintree University Hospitals Airedale Alder Hey Children's Ashford & St Peter's Hospitals Barking, Havering & Redbridge Hospitals

RVL RFF RNJ RDD RN5

-FT -FT FT

London Yorkshire & the Humber London East of England South East

Barnet & Chase Farm Hospitals Barnsley Hospital Barts & the London Basildon & Thurrock University Hospitals Basingstoke & North Hampshire

20 2 8 3 1

13 2 13 2 1

13 5 18 2 2

8 3 15 2 1

15 5 9 3 2

6 2 10 0 0

6 0 10 7 0

3 1 9 3 1

3 0 7 1 1

6 1 8 0 1

3 1 8 3 1

4 0 5 2 1

5 0 6 2 0

2 0 6 1 0

0 0 4 1 0

2 0 9 2 0

Barnet & Chase Farm Hospitals Barnsley Hospital Barts & the London Basildon & Thurrock University Hospitals Basingstoke & North Hampshire

RC1 RQ3 RLU RXL RAE

-FT FT FT FT

East of England West Midlands West Midlands North West Yorkshire & the Humber

Bedford Hospital Birmingham Children's Hospital Birmingham Women's Blackpool Teaching Hospitals Bradford Teaching Hospitals

4 0 0 14 16

2 0 0 7 7

6 1 0 12 14

4 0 0 7 10

4 0 0 2 10

4 1 0 3 4

2 0 0 3 2

0 0 0 1 5

0 3 0 2 3

3 0 0 1 3

1 0 0 2 1

1 0 0 3 2

1 1 0 2 2

3 0 0 2 3

1 0 0 0 1

0 0 0 5 1

Bedford Hospital Birmingham Children's Hospital Birmingham Women's Blackpool Teaching Hospitals Bradford Teaching Hospitals

RXH RXQ RJF RWY RGT

--FT FT FT

South East South East West Midlands Yorkshire & the Humber East of England

Brighton & Sussex University Hospitals Buckinghamshire Healthcare Burton Hospitals Calderdale & Huddersfield Cambridge University Hospitals

15 10 0 11 15

18 2 3 9 12

18 9 8 7 7

15 6 4 5 7

5 1 3 5 9

15 3 2 2 9

8 7 3 2 2

8 1 3 5 10

10 1 3 3 7

7 7 3 4 4

4 3 1 4 6

6 1 3 5 3

5 1 2 3 7

5 3 0 2 3

4 0 1 3 1

2 0 0 1 1

Brighton & Sussex University Hospitals Buckinghamshire Healthcare Burton Hospitals Calderdale & Huddersfield Cambridge University Hospitals

North West London East Midlands

Central Manchester University Hospitals Chelsea & Westminster Hospital Chesterfield Royal Hospital

6 5 6

5 3 0

4 4 1

6 4 3

6 2 2

5 2 1

3 0 2

3 1 3

0 1 2

1 4 0

3 4 2

4 1 2

1 2 2

4 2 1

3 4 2

3 Central Manchester University Hospitals 1 Chelsea & Westminster Hospital 2 Chesterfield Royal Hospital

RW3 FT RQM FT RFS FT

Department of Health Website, UK

Environmental Study 171 swabs -156 grew meropenem resistant Gram-negatives) - 51/171 (29.8%) were positive for NDM-1 UNDERESTIMATION!!!

50 water samples - 14 grew meropenem resistant Gram-negatives) - 2 out of 50 (4%) were positive for NDM-1

W32

S1

S33

S65

April 14th 2011

Delhi chief minister Sheila Dikshit, in denial over the existence of the notorious New Delhi superbug in the city's water, changed tack to play it safe as well.

Her government will now supply free Chlorine tablets to ensure people get safe water. The decision came even as the chief minister insisted that the water supplied by the DJB was "absolutely safe and secure". Dikshit, who chaired a high-powered meeting with representatives from the state and Union government agencies, rejected out of hand a report in the respected medical journal The Lancet Infectious Diseases , that the New Delhi metallobeta-lactamase (NDM)- 1 gene had been found in open water pools, overflowing sewage and even in drinking water samples.

However, there was confusion over the two, apparently conflicting announcements made by the state government.

What is the carriage of NDM-1 is Southern Asia?

• Carriage rates: Pakistan: prevalence of 27.1% in in-patients and 13.8% in out-patients. Perry et al., JAC. 2011. in press

• Extrapolating data from the New Delhi environmental study indicates at least 100-200 million (Walsh et al., LID, 2011)

• Antibiotic Policies • National Surveillance • Encourage International Studies • No link between sanitation and AR resistance

Misconceptions on how antibiotic resistance spreads Hospital Acquired Infections

Community

Environmental Contamination

Sub-lethal concentrations of Ciprofloxacin induce the SOS response Ciprofloxacin

Amikacin

tetracycline

A. Couce and Jesus Blazquez 2009 FEMS Microbiol Rev 531-538

recA:GFP fusion

NDM-1 in Acinetobacter baumannii – A European/Chinese problem?

Molecular characterization of blaNDM-1 in an Acinetobacter baumannii strain isolated in Germany in 2007. (Pfeifer Y, Wilharm G, Zander E, Wichelhaus TA, GĂśttig S, Hunfeld KP, Seifert H, Witte W, Higgins PG). J Antimicrob Chemother.

2011 Sep;66(9):1998-2001.

Indian isolates from 2005 clearly showing multiple copies of NDM-1 (Jones, Toleman, Walsh unpublished data)

India s unsung hero “HE SAID SOME INTERPRETATIONS WERE WORKED INTO THE REPORT WITHOUT HIS KNOWLEDGE.“ SOURCE: THE HINDU 24/8/2010

NDM-1: what lessens must we learn?

• Surveillance must be Global or nothing at all • Surveillance must include typing and molecular biology • Science must NOT be politically tainted • National objectives must be in line with the WHO policies on health • International accountability must be enforced – national audit index based on GDP • Additional tax to work on infectious diseases

Good Indian NDM-1 studies must be encouraged!

An Invitation!

WalshTR@Cardiff.ac.uk

Is it all worth it?

Since first publication No offers for assistance 57 abusive emails and well over 80 negative comments in the India media