ANTIMICROBIAL RESISTANCE AGAIN...antimicrobial resistance” • “Antimicrobial resistance is occurring everywhere in the world, compromising our ability to treat infectious diseases,

ANTIMICROBIAL RESISTANCE (AGAIN)

Martin Cormican, Galway University Hospital and National University of Ireland, Galway

Centre for Health from Environment

@healthfromenvir

Microbiology and Infectious Diseases

@not-evilomonas

Tweet

If antibiotic use is easy, cheap, good for business, makes

for a quiet life, gets you home on time for dinner

“awareness” will not work

The Tragedy of the Commons

• Garrett Hardin

• Science in 1968.

• A group of people share a resource

• Each person makes rational self interested

economic choices

• Each individual better of in short term

• The resource is destroyed

• Every one is worse off long run

The Carbapenem Commons

Carbapenemase Producing

Enterobacteriaceae : 2015

Now Moving on to the Colistin Commons

Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in

animals and human beings in China: a microbiological and molecular biological

study

Lancet Infectious Diseases November 2015

Plasmid-mediated Colistin Resistance in Enterobacteriaceae

mcr-1 gene

Now reported all over the world (not reported in Ireland yet)

Overview of the Talk

• 1. How Big is The Deal ?

• 2. Antimicrobial Resistance – the nature & extent of

the problem

• 3. Accepted Drivers of Antimicrobial Resistance &

Interventions

• 4. Conclusions and Predictions

How Big Is The Deal



the probl

• Resolution adopted by the World Assembly of

Delegates. 83rd General Session, May 2015

Sixty-eighth World Health Assembly

• The Sixty-eighth session of the World Health

Assembly (WHA) Geneva 18–26 May 2015.

• “endorsed a global action plan to tackle

antimicrobial resistance”

• “Antimicrobial resistance is occurring

everywhere in the world, compromising our

ability to treat infectious diseases, as well as

undermining many other advances in health

and medicine.”

How Big Is The Deal

OIE & AMR

“One Health’

How Big is The Deal : Closer to Home

How Big is the Problem of Antimicrobial

Resistance?

Transatlantic Task Force On Antimicrobial Resistance

Joint EU US Group

Established in 2009

How Big is the Problem of Acquired

Antimicrobial Resistance?

UK Chief Medical Officer Dame Sally Davis

“Antimicrobial resistance poses a catastrophic threat. If

we don’t act now, any one of us could go into hospital in

20 years for minor surgery and die because of an

ordinary infection that can’t be treated by antibiotics”

Closer To Home

At a Day to Day Level

At a more Human Level

64 Year Old Diabetic Man In ICU

Major Emergency Abdominal Surgery 30 Days Ago Following RTA

Complications Required Re-operate 15 Days Ago

Abdomen could not be closed

Multiple Antimicrobial Agents for Infection

On a ventilator, renal dialysis

Now has blood culture positive for K. pneumoniae &

Stenotrophomonas maltophilia


Acquired Antimicrobial Resistance?

The K. pneumoniae

Resistant to: (Intrinsic/Acquired)

Amoxicillin, Amoxicillin/Clavulanate,

Piperacillin/Tazobactam, Cefotaxime, Ceftazidime,

Aztreonam, Meropenem, Gentamicin, Tobramycin,

Amikacin, Ciprofloxacin, Tigecycline

Susceptible to

Colistin, Fosfomycin

Antimicrobial Resistance – Day in Day

Out


Intrinsic Antimicrobial Resistance?

The Stenotrophomonas maltophilia

Resistant to: (Intrinsic/Acquired)

Amoxicillin, Amoxicillin/Clavulanate,

Piperacillin/Tazobactam, Cefotaxime, Ceftazidime,

Aztreonam, Meropenem, Gentamicin, Tobramycin,

Amikacin, Tigecycline

Susceptible to

Levofloxacin, Cotrimoxazole

How Big is the Problem of Antimicrobial

Resistance?

The focus of Public Health Concern is Acquired

Antimicrobial Resistance

But Intrinsic Resistance Also Matters In Modern Health

care because we make people vulnerable even to

Stenotrophomonas maltophilia

It’s a Big Problem For People Who Were

Already Sick

For people with major illness (very complex ICU infection, leukaemia

etc.)

- infection is already much harder and more expensive to manage

- Occasionally we see infection that is near impossible to treat

- This will get more common & more difficult

- The major problem now is with Gram-negatives

-

It’s a Significant Problems Even in

Common Non Life-threatening Infection

For people with

Cystitis /Dysentery/Skin Infection:– harder to guess which antibiotic

will work

Harder to find an oral option that will work to treat them at home

Next Steps

- This will get more common & more difficult

- The major problem now is with Gram-negatives

- Its bad and getting worse though I am not sure it’s a catastrophe

Is Antimicrobial Resistance Impacting on

Animal Health Care ?

I don’t know but I suppose it should be

Some Material on Horses and Dogs

We Know that 10 day old chicks carry ESBL E. coli and

Fluoroquinolone-resistant E. coli

But we seem to lack much information on this




the problem


Interventions


1915

Acquired Antimicrobial Resistance

Evolution and Environment

• 1915 – Baseline Biodiversity

• Diversity of life-forms based on largely conserved

metabolic motifs but with some critical differences

e.g.

• 1. Cell Walls: different or absent in eucaryotes

• 2. Protein Synthesis: Prokaryote / Eucaryote but some Points

of Difference (e.g. ribosomes 70S v 80S)

• 3. Points of potential targets for selective toxins (magic bullets)

What Does The Theory of Evolution Predict ?

• If Targets for Selective Toxicity Exist ?

• Selective Toxins Focused on Points of Difference Would

Confer Advantage

• So Selective Toxins Should Emerge

• And so they did !

• And Fleming, Waksman, Brotzu Found Them Easily

• (penicllins, streptomycin, cephalosporins)

Selective Toxins Become Therapeutic

Antibiotics

• Cell Wall Synthesis

• Beta-lactams

• Glycopeptides

• Protein Synthesis

• Streptomycin and other aminoglycosides: Inhibit initiation and cause misreading of mRNA

• Tetracyclines: Binds to the 30S subunit and inhibits binding of aminoacyl-tRNAs

(prokaryotes)

• Chloramphenicol: Inhibits the peptidyl transferase activity of the 50S ribosomal subunit

(prokaryotes)

• Erythromycin: Binds to the 50S subunit and inhibits translocation (prokaryotes)

Are The Synthetic Antimicrobial Agents

(Ciprofloxacin) Different ?

• Probably Not

• Similarly acting agents occur naturally in the general

environment

• Kwak et al. AAC, 2013

Let’s Go Back to The Theory of Evolution

• If Selective Toxins Are Present In an Environment

• What Would You Predict Should Evolve ?

• Mechanisms to inactivate/block /circumvent selective

toxins

• And so they did !

Naturally Occurring Systems for Dealing

With Selective Toxins -1

• Cell Wall Synthesis

• Beta-lactams – beta lactamases

• Glycopeptides - alternative cell wall synthesis pathways

• Protein Synthesis

• Streptomycin and other aminoglycosides: aminoglycoside modifying enzymes/efflux pumps

• Tetracyclines: efflux pumps

• Chloramphenicol: modifying enzymes, efflux pumps

• Erythromycin: efflux pumps

• Fluoroquinolones (synthetic) – efflux pumps and blocking proteins

Summary So Far

• 1915 –

• There Were Antibiotics In the World

• There Were Antibiotic Resistance Mechanisms in the

World

• But the Were Mostly In the Soil & Sewer But Not in

the Clinic

Nothing is Simple

In The People & the Horses Marching up to

the Somme

• 1915 – Gut and Skin Commensals and Major

Bacterial Pathogens of the People & Animals

• Lived in a Place Where There Was

Continuous Intense exposure to immune

mediated attack

• They Had Not Seen an Antibiotic in a Million

Years

• Theory of Evolution Predicts ?

• Little In the Way of Systems to Inactivate

Selective Toxins –

What We Did In the Last 90 Years

• Identified pre-exisiting selective toxins (from

environment)

• Introduced them in high concentrations into the place

where human /animal bacteria live

• So most of the “wild type” of these bacteria died in

hours or days in those people


• But We Live of Soil & Water

• Environmental organisms and their DNA are swallowed

• Human and animal bacteria go into the sewer and the

back to us

• Genes coding for anti-toxin systems transfer by chance

now and again into human /animal bacteria

• All the “wild type” human and animal bacteria are

killed by the antibiotic


• So Now We Have Human and Animal Bacteria that

Have Picked Up Resistance Genes from their buddy’s in

the soil & water

• And We Have Developed Very Good Systems to Spread

them around ?

What is Dr. Charles Deleucena Meigs is

remembered for

?

• Refusal to believe that a doctors hands

could carry disease

• “doctors are gentlemen and a

gentleman’s hands are clean”

• (I don’t know if he though vets were

gentlemen)

Why Does An Evolutionary Perspective

This Matter ?

Where Are The New Classes of Antimicrobials ?

Why Does An Evolutionary Perspective This

Matter ?

• Antibiotic Use In Humans and Animals and Resulting

Environmental Contamination do not make

resistance or resistance genes

• Antibiotic use in human and animals make resistance

matter

Why Does An Evolutionary Perspective This

Matter ?

• Its not simply “lack of investment”

• New really useful antimicrobial agent are intrinsically hard to find because

• Critical points of metabolic difference were always a limited resource

• Those points of difference became a focus of adaptation/counter adaptation

in the general environment

• We have already found and already wasted most of them

• There is probably no new “penicillin” to discover if it could be

synthesised it would have been synthesised long ago by a

fungus or a streptomyces




the problem


Interventions


Antibiotic Use: How Many Tonnes of

Antibiotics Are Used Per Year ?

• About 200 000 Tonnes

• (probably a serious under-estimate)

• The World Is Awash With Antibiotics

• Disinfectant

• “Snake Oil”

Dissemination of Bacteria: Why do we find it so

difficult to hand hygiene & other IPC activities ?

Anthropology Not Microbiology

• Because we are human

• Because we can’t perceive the harm we do

• Because we can’t be held accountable for the harm we do

• Contrast with Error in prescribing / drug administration

And In the Wider World : What A Good Way to Build

Antibiotic Resistance : In Humans

46

And In the Wider World : What A Good Way to Build

Antibiotic Resistance: In Animals

47

And to To Spread It All Over the World

48

And to To Spread It All Over the World : Trade in Live

Animals

• The move towards

Positive (white) Lists

49

The Current Situation : EARS-NET S. aureus

EARS-NET ESBL E. coli

EARS-NET ESBL K. pneumoniae

CPE Reference Lab: 2014

CPE Reference Lab: 2015




the problem


Interventions


So How Are We Doing So Far ?

Very Very Badly

AMR is a Global Problem

&

AMR is a Wicked Problem

&

AMR is Linked to Poverty & Inequity

What Works ?

One World – One Health

Clear Enforced National Mandate Restricting Prescribing

Clear Enforced National Mandate For De-escalation

Targets for Change

Do We Have the Stomach For It

How Serious Are We?

Will We Pick the Low Hanging Fruit : No

We Know That A High Proportion of Dispensed Antimicrobial

Agents (an other medicines) are Not Used

We know that they are often disposed of in landfill and down the

toilet

The Department of Health Has Done Nothing to address this

What Does NOT Work ?

“Raising Awareness”

“Surveillance”

“More research”

Their Value is to Motivate and Guide Action and to Measure

Effect

The Trajectory

• We write reports & papers

• We do too little too late

The Overgrazing Continues

The Commons Continues To Deteriorate

The Trajectory

But It Does NOT Have to Be that Way

Conclusions: What Can One Doctor

/Veterinarian Do?

• Avoid unnecessary use in our own practice

• Use according to guidelines when we use

• Encourage Patients / Owners To Think of Antibiotics as a

balanced risk not an soft option

• Encourage family and colleagues to think of antibiotics as a

balanced risk not a soft option

• Hand hygiene ?

• But none of this is easy

Conclusions: What Can One Veterinarian

Do?

• Power concedes nothing without a demand. It never did and

it never will.

• Agitate, agitate, agitate

• (or Advocate)

• Thank you

Back to Where We Started

Tweet

If antibiotic use is easy, cheap, good for business, makes

for a quiet life, gets you home on time for dinner

“awareness” will not work

not-evilomonas@cormican_martin

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ANTIMICROBIAL RESISTANCE AGAIN...antimicrobial resistance” • “Antimicrobial resistance is occurring everywhere in the world, compromising our ability to treat infectious diseases,