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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
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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
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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
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The Carbapenem Commons
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Carbapenemase Producing
Enterobacteriaceae : 2015
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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)
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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
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How Big Is The Deal
• 1. How Big is The Deal ?
• 2. Antimicrobial Resistance – the nature & extent of
the probl
• Resolution adopted by the World Assembly of
Delegates. 83rd General Session, May 2015
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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.”
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How Big Is The Deal
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OIE & AMR
“One Health’
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How Big is The Deal : Closer to Home
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How Big is the Problem of Antimicrobial
Resistance?
Transatlantic Task Force On Antimicrobial Resistance
Joint EU US Group
Established in 2009
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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”
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Closer To Home
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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
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At a Day to Day Level
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
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Antimicrobial Resistance – Day in Day
Out
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At a Day to Day Level
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
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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
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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
-
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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
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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
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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
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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
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1915
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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)
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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)
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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)
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Are The Synthetic Antimicrobial Agents
(Ciprofloxacin) Different ?
• Probably Not
• Similarly acting agents occur naturally in the general
environment
• Kwak et al. AAC, 2013
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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 !
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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
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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
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Nothing is Simple
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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 –
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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
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What We Did In the Last 90 Years
• 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
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What We Did In the Last 90 Years
• 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 ?
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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)
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Why Does An Evolutionary Perspective
This Matter ?
Where Are The New Classes of Antimicrobials ?
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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
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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
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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
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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”
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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
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And In the Wider World : What A Good Way to Build
Antibiotic Resistance : In Humans
46
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And In the Wider World : What A Good Way to Build
Antibiotic Resistance: In Animals
47
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And to To Spread It All Over the World
48
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And to To Spread It All Over the World : Trade in Live
Animals
• The move towards
Positive (white) Lists
49
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The Current Situation : EARS-NET S. aureus
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EARS-NET ESBL E. coli
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EARS-NET ESBL K. pneumoniae
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CPE Reference Lab: 2014
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CPE Reference Lab: 2015
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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
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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
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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
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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
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What Does NOT Work ?
“Raising Awareness”
“Surveillance”
“More research”
Their Value is to Motivate and Guide Action and to Measure
Effect
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The Trajectory
• We write reports & papers
• We do too little too late
The Overgrazing Continues
The Commons Continues To Deteriorate
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The Trajectory
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But It Does NOT Have to Be that Way
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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
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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
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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