Antibiotic Resistance a modern catastrophe of our …users.ox.ac.uk/.../documents/resistance_for_web_2014.pdfAntibiotic Resistance – a modern catastrophe of our own making Dr Nicola

Antibiotic Resistance – a modern catastrophe of our own making

Dr Nicola Fawcett Registrar Acute/General Medicine

MRC Research Fellow, Nuffield Dept. of Medicine , University of Oxford [email protected]

Slides for the Web

More information, reading material etc. can be found via twitter page - @drnjfawcett

mailto:[email protected]

Image Attributions/Sharing

• Please email/ask me if you want to use the original slides! I’m more than happy.

• Images from the web and articles used for presentation and teaching – if used for sharing, external presentations or commercial use, please give credit to the original creator, review copyright and act accordingly.

• Arnie, Sean Bean, Dr Kelso, Indy and other images – IMDB, www.hbo.com, scrubs.wikia.com

• Wardround – www.visualphotos.com

• Antibiotic Resistance cartoon – cartoonstock.com, purchased for personal nonprofit use in social media.

• Please contact me if you have any queries about the available pictures and attributions.

Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

http://www.hbo.com/

http://www.visualphotos.com/

Chief Medical Officer Sally Davis


Antimicrobial Resistance – the view from the world of medicine

RESISTANCE

You’ve been telling us for years that antibiotic resistance is a problem –

what problem? I haven’t seen anything in my practice to make it an

issue. Sounds like a whole load of scare-mongering by microbiologists in

front of their petri-dishes to me


UK: “An elderly person coming in to hospital

confused or not right is incredibly hard to

assess, and in my experience ‘geri-fix’ – co-

amoxiclav and iv fluids - does wonders . The

simple truth is that antibiotics do work”

In France the healthcare system means that if

a patient pays to see a GP, they expect

something for it, plus the GPs make more

money if they prescribe something – of course

they’re going to use more antibiotics

“I know the guidance, but I only have 5

minutes with a patient , it’s Friday afternoon–

anyone who comes in with a cough and

feeling unwell gets antibiotics, they’re safe

over the weekend and next person please

Because everyone gets antibiotics when

they see a Doctor for a cough, they expect

antibiotics next time and aren’t happy

when I advise them they don’t need it

Antibiotics around the world- a victim of their own success?


China “the most commonly used

antibiotic in their hospital were

carbapenems

“When I was in Malta, the usual ‘UTI’ was a

granny with an ESBL – everyone who came

in got bunged straight on IV Meropenem”

Antibiotics around the world- a victim of their own success?

On elective in Nepal: honestly, antibiotics are

like sweeties, you go to the local corner shop

saying you feel unwell and they give you a bag

of pills of which one is likely to be a steroid, one

a painkiller and then a couple of antibiotics for

good measure as well (though god knows if

they’re real or not…)

Iraq: Doctors try and give patients the basic

antibiotics but if the patient /family are paying,

then often they’ll demand ‘the strongest

antibiotics’ and think Doctors are fobbing them

off by giving them anything other than IV

meropenem


How do you persuade clinicians to reduce their antibiotic prescriptions?

Strategies:

• Do not start?(where this is a safe choice – the patient is not that ill)

• Reduce the use of certain classes? of antibiotic - especially broad spectrum – eg minimise carbapenem use

• Reduce the duration? (where there is good evidence that shorter courses are as effective as others)


• In a hospital setting, it is important not to be too restrictive!


Factors perceived by Clinicians to change antibiotic prescribing ECCMID Abstract 2014 Fawcett, N, Jones, N

hospital clinicians place much greater importance on adverse events

to patients directly under their care versus a future theoretical risk to

patients Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

Decision Making in the Acute Setting

RISKS POTENTIAL BENEFITS

?

?

Risk to the population of drug-resistant infection

• Risk of untreated or undertreated infection • Risk of antibiotic-related side effects • Risk of future drug-resistant infection • Impact on hospital and patient experience

Antibiotic or no antibiotic Spectrum Duration

?INFECTION Factors:

Harm to my patient


Amoxicillin

1st gen cefalosporins (eg. Cefalexin)

Penicillin

Beta-lactam based antibiotics

The Antibiotic Arsenal


Amoxicillin


3rd gen cefalosporins (eg. Ceftriaxone)

Penicillin

Carbapenems




Amoxicillin


3rd gen cefalosporins (eg. Ceftriaxone)

Penicillin

Carbapenems




Macrolides (eg Clarithromycin) Tetracyclines (eg. Doxycycline) Metronidazole Etc etc

Glycopeptides (eg. Vancomycin)

Quinolones (eg. Ciprofloxacin)

Aminoglycosides (eg Gentamicin)

The Antibiotic Arsenal - Continued


Shotgun, hand grenade, Arnie?

Likelihood of cure Collateral Damage

Shotgun 80-85% Minimal *

Hand Grenade 90% Large *

Arnie 100% Crater *

Risk : Benefit Analysis

Working Diagnosis: UTI Common Organisms: E. Coli Klebsiella Enterococci Proteus Pseudomonas

* - limited evidence base, subjective opinion, guesswork Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

Greece Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

Shotgun, hand grenade, Arnie?

I quite fancy a curry for lunch

Likelihood of cure Collateral Damage

Shotgun 5% Minimal *

Hand Grenade 30% Large *

Arnie 75% Crater *

* - limited evidence base, subjective opinion, guesswork Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

The message about combating resistance has been mixed and unclear

More? Less? Longer? Shorter? What do I do?


Albrich et al, Emerg Infect Dis. 2004

Evidence for factors associated with reduced risk of resistance in isolates infection • Low country-wide antibiotic

use in humans • Low antibiotic use in animal

husbandry • Robust healthcare systems


What do we do about it?

• Stop selecting for resistant bugs and stop disrupting the indigenous gut flora which is holding them in check

• Use the smallest amount of effective antibiotic for the shortest possible time

Best method of reducing resistance depends on the mechanism of resistance

• Blast Them

• Fool Them

• Try to Outwit Them

• Stop Irritating Them


The dialogue about resistance (and what to do to combat it) has to acknowledge the organism and setting of interest

To prevent penicillin resistance developing in the strep. Pneumoniae causing pulmonary infection in this patient = blast it with high dose antibiotic therapy with concentration above MIC

To prevent resistance developing in the streptococcus in the throat of the patient – avoid antibiotics altogether

To prevent resistance to macrolides developing in strep. on a population level, minimise the use of macrolides

To prevent resistance developing in the faecal bacteria – minimise antibiotic use, especially antibiotics with activity against gram negative organisms (?)


Which organism are we most worried about?


Inhibition of growth –sensitive to: -Co-amoxiclav -Cefalexin -Ceftriaxone -Meropenem

No inhibition of growth -resistant to Ampicillin

Sensitive to: Ciprofloxacin Tetracyclines (eg. Doxycycline) Gentamicin

Resistant to: Erythromycin Vancomycin

E. coli from Sample A1


Resistant to Ampicillin, Co-Amoxiclav Ceftriaxone… (3rd Gen Cefalosporin) – extended spectrum beta lactam antibiotic

Resistant to: Erythromycin Vancomycin, Gentamicin, Tetracyclines, Quinolones, Macrolides..

Sensitive to Meropenem…

K. pneumoniae from Sample A3

Klebsiella displays likely Extended-Spectrum-Beta-Lactamase resistance - ESBL


Colonisation • Prevalence of ESBL E.coli in healthy population

detected on faecal sample screening:

Setting %ESBL Ref

Spain 1991 Outpatients 0.7% Valverde et al 2004

Spain 2003 Outpatients 5.5%

Spain 2003 Healthy Volunteers 3.7% (65% CTX-M)

Japan Healthy Volunteers 6.4% (92% CTX-M) Yamamoto et al 2011

Saudi Arabia Healthy volunteers 13.1% Kader et al 2007

Thailand Rural Community 58.2% CTX-M Sasaki et al 2010

(Although actual sensitivity to low numbers of organisms unknown)


Europe data: 2008-2011 European Antimicrobial Surveillance System (EARSS)

Asia-Pacific: -2009 data Yen-Hsu Chen et al, Journal of Infection April 2011

USA – 2009 data

Bhusal et al, Chemotherapy, 2011

Percentage of ESBL-Producing E.coli Invasive Isolates

- Worldwide data

5% 10%

23%


Europe data: 2008-2011 European Antimicrobial Surveillance System (EARSS)

Asia-Pacific: -2009 data Yen-Hsu Chen et al, Journal of Infection April 2011

USA – 2009 data

Bhusal et al, Chemotherapy, 2011

Percentage of ESBL-Producing E.coli Invasive Isolates

- Worldwide data

5% 10%

23%

65%

3%

29%


Carbapenem-resistant Enterobacteriaceae cases referred to HPA Colindale

CMO Annual Report :Volume 2, 2013 Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

Penicillins

Daptomycin Tigecycline Colistin

Carbapenems

3rd Gen Cefalosporins

Cefalosporins

We’re fine!

It’s been going on for years, why are we suddenly getting so worked up about things?


Penicillins


Carbapenems


Cefalosporins

We’re fine!



Penicillins


Carbapenems


Cefalosporins

??

…



Where is the ‘Collateral Damage of Antibiotic Use?

• The Gut Microbiome

• Reservoir of diverse range of bacteria

• Significant source of colonisation with resistant bacteria

• Subject to selection pressure during antibiotic therapy


0

1

2

3

4

5

6

7

8

Quinolones Cephalosporins Penicillins Macrolides Sulphonamides Tetracyclines

5.65 4.47

3.25 2.55

1.84

0.91

prior exposure to antibiotic and risk of C. diff

Deshpande et al 2013

30, 184 patients


0

5

10

15

20

25

Clindamycin - 20.4

prior exposure to antibiotic and risk of C. diff

Deshpande et al 2013

30, 184 patients


Antibiotics can cause long term, and possibly irreversible changes in the gut microbiota

Jernberg et al 2007

Single course of Clindamycin administration

Number of Bacteroides clones

Number with resistant phenotype

No clindamycin

Number with resistant phenotype

2 years later!

The difficulty with culture…. One species, one antibiotic... Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

Mice not inoculated with resistant bacteria Mice inoculated and given saline injection Mice given iv ampicillin Mice given oral ampicillin

Mode of administration may play a significant part – IV vs PO Ampicillin –effect of faecal resistance gene carriage in mouse model

Ampicillin is renally excreted only – iv will theoretically not have significant GI levels


Zhang et al, Antimicrobial Agents and Chemotherapy 2013

Traditional model of resistance acquisition and spread

Pathogen acquisition

Antibiotic treatment and selection pressure





Incomplete Treatment

Successful eradication

Persistence of resistant organism







Persistence of resistant organism Transmission of resistant organism







Persistence of resistant organism Transmission of resistant organism

Relevant in organisms where: • Vertical transmission of

resistance is dominant • Predominantly human

reservoir • Eradication is possible • Significant persistence of

infecting organism after treatment

• M. tuberculosis • S. aureus • M. abscessus • N. gonorrhoeae • (Pseudomonas)


Acquired Resistance

www.cartoonstock.com – Nick Kim, purchased for social media use. . If sharing please review their policy


http://www.cartoonstock.com/

Nonpathogenic/environmental With endogenous antibiotic resistance element

Co-existence under selection pressure

‘Capture event’ Under antibiotic selection pressure Horizontal gene transfer





Integration into a highly transmissible vector

Epidemic Spread of mobile genetic elements between strains and/or species

Increased likelihood of acquiring resistant infection

Global increase of resistance elements





Integration into a highly transmissible vector

Epidemic Spread of mobile genetic elements between strains and/or species

Increased likelihood of acquiring resistant infection

"the spread of NDM-1(carbapenemase) is probably due to the high mobility of the NDM-1 plasmids as opposed to clonal dissemination"

Sao Paulo “The spread of the KPC (carbapenemase) gene may be facilitated by its localisation on plasmids and transposons and also by efficient clones”

Mataseje et al 2014 Lopez-Camacho et al 2014

Global increase of resistance elements

• Mobile-genetic-element mediated resistance

• Can be up/downregulated and easily shared

• Often little fitness cost of resistance


Where is it coming from? Community Reservoir: • Prevalence of ESBL E.coli in Nursing Home in N. Ireland 40.5%

– 51% of carriers had no history of hospital admission Abroad: • Travellers in Sweden-carriage of ESBLs:

– Prior to travel 4% – After travel 32% (Travel to India – 82%) – Found in travellers without GI symptoms

Non-human sources: • Retail meat –detected ESBL/CMY producing E.coli

– Sevilla 67% - Pittsburgh 85% Environment: • Sewage from hospital waste water in Lebanon: multiple GNRs with different

resistance mechanisms • Water sources in India- high levels of NDM-carrying isolates… (Tim Walsh) • Report of measured concentration of ciprofloxacin in factory efflux at near serum

therapeutic range…

Rooney et al, JAmChem 2009, Ostholm Balkhed ECCMID abstract, Doi et al Clin Microb Infect 2010, Original slides - N Fawcett, Nuffield Dept of Medicine, Oxford - [email protected], @drnjfawcett

Antimicrobial resistance as a result of widespread anthropogenic alteration and contamination of our biosphere with antibiotics

Davies et al Microbiology and Molecular Biology Reviews 2010


Antimicrobial Resistance – where are we?

Us

Pan-Drug-Resistant E.coli


“End to modern medicine as we know it”

Antimicrobial Resistance – Where Are We?




UK

Spain/Greece

India/Asia




Run Faster? New Antibiotics





Stop the boulder? Reduce antibiotic selection pressure Infection prevention measures



Antibiotic Resistance – Where Are We?





Antibiotic Resistance – Where Are We?




Conclusions

• Resistance is spreading pandemically via selection of high-fitness strains, mobile genetic elements…

• Colonisation and amplification of resistant elements occurs with antibiotic therapy

• Resistance spread is a consequence of the anthropogenic global contamination of our biosphere with antibiotics

• More evidence is needed on the selection effect of antibiotics in vivo, to inform how to minimise resistance selection and spread


Documents

Antibiotic Resistance a modern catastrophe of our …users.ox.ac.uk/.../documents/resistance_for_web_2014.pdfAntibiotic Resistance – a modern catastrophe of our own making Dr Nicola