Today

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Todays talk

• Dimensions of AB resistance
• History of AB resistance
• Biology of AB resistance
• Biology of antibiotic action and measurement
• Genetics
• Biochemistry
• Selection
• Some guiding questions and concepts

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Dimensions of Antibiotic Resistance

• Bacterial species
• Type of transmission hospital or community
• Antibiotic
• Genetic mechanism of resistance how does the bug
  get the genes to be resistant?
• Biochemical mechanism of resistance what does
  the bug do to be resistant?
• Mechanisms of selection for resistance
• Individuals
• Populations
• Study design to assess these mechanisms

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History of Antimicrobial Resistance
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Early principles Paul Ehrlich

• The therapia sterilisans magna consists in this,
  that by means of one or at most two injections
  the body is freed from the parasites. Here,
  therefore, the old therapeutic remedy is
  applicable . frapper fort et frapper vite
• A further advantage of combined therapy is, that
  under the influence of two different medicines
  the danger of rendering the parasites immune to
  arsenic, which naturally would be a very great
  obstacle in connexion with further treatment, is
  apparently greatly minimized.

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1930 1940 1950 1960 1970 1980 1990
2000
Sulfa Penicillin
Strept Tetra
Chlora
Erythro
Oxa/amp/ceph
Vanco
Genta

Trimethoprim
3rd gen cephalosporins

Fluroquinolones

Carbapenems
ESBLs
AmpCs
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Resistance comes fast
J. Davies 1997
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Resistance increases quickly
P. aeruginosa resistant to imipenem
P. aeruginosa resistant to quinolones
K. pneumoniae non-susceptible to 3rd
cephalosporins
Source NNIS DATA Clinics Chest Med. 20303-315
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Resistance goes up quickly (2)
Methicillin-resistant Coagulase-negative Staph
Methicillin-resistant S. aureus
Vancomycin-Resistant enterococci
Source NNIS DATA Clinics Chest Med. 20303-315
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Still growing Resistance in Streptococcus
pneumoniae in US
G Doern et al., Clin Inf Dis. 2005
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Geographic variation in antibiotic resistance
H. Goossens et al. 2005 Lancet
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Geographic Variation Resistancein 1999
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The Tragedy of The Commons
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Resistance goes down slowly, if at all
39 R
45 R
V Enne et al., Lancet 2001
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Resistance goes down slowly, if at all
Hennessy et al. 2002, CID
30 decline in prescribing after initial
intervention 25 after expanded
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But in hospitals, changes can move faster
Dunkle et al. Amer J Med 1981
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Biology of Antimicrobial Resistance
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How do antibiotics kill?

• Static v. cidal
• Bacteriostatic prevent cell division (e.g. by
  preventing protein synthesis)
• Bactericidal kill bacteria directly
• Cidal drugs often kill only dividing bugs
• Cell wall synthesis inhibitors
• Others
• This makes treatment of latent infection
  especially difficult (TB)

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Antibiotics and the immune system

• Immune responses required to kill alongside
  bactriostatic drugs
• Also for many bactericidal drugs phenotypic
  resistance

Wiuff et al. AAC 2005
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Normal Flora
S. pneumoniae H. influenzae N. meningitidis
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Normal flora Consequences

• Treatment exerts selection on innocent
  bystanders
• Most of the harm done by use of a drug may be on
  species OTHER than the target of treatment
• Optimal dosing for treatment ? optimal to prevent
  resistance
• Most of the exposure of a given species to a
  given drug may be due to treatment of OTHER
  infections

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Measuring resistance Minimal Inhibitory
Concentration (MIC)

• Broth microdilution

• Etest

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MIC is a simplification
Regoes et al. AAC 2004
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Limitations of MIC

• Subpopulations
• Depends on in vitro conditions pH, etc not
  necessarily same as in vivo
• One parameter summary of the curve
• Ignores physiologic variation

Regoes et al. AAC 2004
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Biological Aspects of Resistance

• Genetics how is drug resistance coded?
• And how can it move from one bug to another?
• Think of floppy disk, memory stick, punch card
• Biochemistry/mechanism what does a bug do to
  become resistant?
• Think of iTunes, RealPlayer, Microsoft Media
  Player
• How resistance is selected how do we increase
  the frequency of resistant bugs?
• Block that metaphor!

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Intrinsic resistance

• All members of a species are resistant, and have
  been since before clinical use
• Tuberculosis and penicillin naturally encodes
  beta-lactamase
• Vancomycin-producing species and vancomycin
  alters its cell wall to be insensitive (same as
  resistance in targets!)
• Dont activate prodrug
• Isoniazid or pyrazinamide and non-mycobacteria
  not chemically altered to become active

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Genetic Mechanisms of Resistance Acquisition
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Implications

• Mutation easy to get a resistant strain in
  almost any patient mutation frequencies 10-7
  10-10
• Unless multiple mutations are required to confer
  resistance!
• Examples Tuberculosis, HIV
• Other mechanisms
• Very complex mechanisms of resistance can evolve,
  because they can move as a block from one bug to
  the next
• Can even transfer from one species to another
• Emergence of a resistant bug in a single host is
  unlikely, unless a mix of resistant bugs and
  sensitive bugs is present

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Epidemic Plasmids
Courtesy Tom OBrien, BWH
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Integrons

• System for combining resistance (and other) genes
• Can take up new genes via integrase and add them
  to the package
• Often on transposons or plasmids

www.mmb.usyd.edu.au/coleman/
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Biochemical mechanisms

• Reduced permeability
• Efflux
• Degradation
• Detoxification
• Target alteration enzyme
• Target alteration mutation
• Target amplification
• Inactivate the activator of the prodrug

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Mechanisms their consequences

• Most mechanisms are quite specific to one drug or
  class of drugs
• Enzymes to alter drug or target
• Target changes or amplification
• A few mechanisms confer resistance to more than
  one class of drug
• Efflux pump MDR transporter

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Mechanisms

• High-level resistance completely resistant to
  any achievable concentration
• Partial resistance small change in MIC

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Mechanisms of selection
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How Antimicrobial Use Increases Resistance
Mechanisms

• Acquired Resistance selection within host
• Patient infected with a susceptible organism
• Treatment selects a resistant variant

Rx
Emerg Inf Dis 2002 8347
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How Antimicrobial Use Increases Resistance
Mechanisms

• Primary Resistance Selection in host
  population
• Patient infected with a resistant organism
• Competitive mechanism Treatment selects by
  reducing transmission of susceptible infections

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How Antimicrobial Use Increases Resistance
Mechanisms

• Increasing susceptibility to colonization
• Patient carries a normal flora
• Treatment increases susceptibility to
  colonization by opening ecologic niche

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Summary of Mechanisms of Selection of Resistance
by Abx
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Is antibiotic use harmful to individuals?
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Co-selection

• Dental fillings installed and removed from
  experimental monkeys

Summers 1993 AAC
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Concepts and questions

• Antibiotic resistance is interesting how bad is
  it?
• How can we measure the costs? Compared to what?

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What can we do to/for an individual patient to
prevent resistant infections?
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Why have some kinds of drug resistance increased
fast, others slowly or not at all?
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What can we do to the population as a whole to
reduce the risk of reistant infections?
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In what circumstances does doing what is best for
the patient

• Increase the burden of resistance in the
  community?
• Reduce the burden of resistance in the community?
• Both but on different time scales?

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What would happen if we stopped using antibiotics
tomorrow?

• To disease?
• To resistance?

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