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Today’s 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
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
History of Antimicrobial Resistance
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.
GC, H. flu
ADD DHFR
ADENYLATE
E.coliADD ß-LACTAMASE
METHYLATE RIBOSOME
ACETYLATE
EFFLUX
PHOSPORYLATE
S. pneumoADD PBPS. aureusADD ß- LACTAMASE
All Gram negsADD DHTS
1930 1940 1950 1960 1970 1980 1990 2000
GC Mening
VRE
QM
RSA
Pseud
Kleb
E.coli
ESBLs
AmpCs
? VMRSA
Sulfa
Penicillin
Strept
Tetra
Chlora
Erythro
Oxa/amp/ceph
Vanco
Genta
Trimethoprim
3rd gen cephalosporins
Fluroquinolones
Carbapenems
MRSAADD PBP
MUTATE
Resistance comes fast
Antibiotic Discovery Clinical Use
Resistance identified
Penicillin 1940 1943 1940
Streptomycin 1944 1947 1947,1956
Tetracycline 1948 1952 1956
Erythromycin 1952 1955 1956
Vancomycin 1956 1972 1987
Gentamicin 1963 1967 1970
J. Davies 1997
P. aeruginosa resistant to imipenem
K. pneumoniae non-susceptible to3rd cephalosporins
ICU PatientsNon-ICU Patients
P. aeruginosa resistant to quinolones
Source: NNIS DATA Clinics Chest Med.20:303-315
0
2
4
6
8
10
12
14
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Year
Per
cent
Res
ista
nce
0
5
10
15
20
25
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Year
Per
cent
Res
ista
nce
0
5
10
15
20
25
30
35
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Year
Per
cent
Res
ista
nce
Resistance increases quickly
Methicillin-resistantS. aureus
Methicillin-resistantCoagulase-negative Staph
Vancomycin-Resistantenterococci
ICU PatientsNon-ICU Patients
Source: NNIS DATA Clinics Chest Med.20:303-315
0
10
20
30
40
50
60
1989 1991 1993 1995 1997 1999 2001
Year
Per
cent
Res
ista
nce
0102030405060708090
100
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Year
Per
cent
Res
ista
nce
0
5
10
15
20
25
30
35
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Year
Per
cent
Res
ista
nce
Resistance goes up quickly (2)
Still growing: Resistance in Streptococcus pneumoniae in US
G Doern et al.,
Clin Inf Dis. 2005
Geographic variation in antibiotic resistance
H. Goossens et al. 2005 Lancet
Geographic Variation Resistancein 1999
0
0.1
0.2
0.3
0.4
0.5
CA CT GA MD MN NY OR TN
Pro
port
ion
Pen
icill
in
Res
ista
nt
State
The Tragedy of The Commons
Resistance goes down slowly, if at all
V Enne et al., Lancet 2001
39% R 45% R
Resistance goes down slowly, if at all
Hennessy et al. 2002, CID
~30% decline in prescribing after initial intervention~25% after expanded
But in hospitals, changes can move faster
0%
5%
10%
15%
20%
25%
30%
35%
Jun-79
Jul-79 Aug-79
Sep-79
Oct-79
Nov-79
Dec-79
% in
fect
ed w
ith
gen
tam
icin
-re
sist
ant
MR
SA
Dunkle et al. Amer J Med 1981
Biology of Antimicrobial Resistance
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)
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
“Normal” FloraS. aureus
GNR(E. coli, KlebsiellaEnterobacter)
Enterococcusfaecium
S. pneumoniaeH. influenzaeN. meningitidis
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
Measuring resistance: Minimal Inhibitory Concentration (MIC)
• Broth microdilution • Etest
MIC is a simplification
Regoes et al. AAC 2004
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
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!
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!)
– Don’t activate prodrug• Isoniazid or pyrazinamide and non-mycobacteria:
not chemically altered to become active
Transformation
Plasmidtransfer
Genetic Mechanisms of Resistance Acquisition
Mutation
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
Courtesy Tom O’Brien, BWH
Epidemic Plasmids
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/
• Reduced permeability• Efflux• Degradation• Detoxification• Target alteration: enzyme• Target alteration:
mutation• Target amplification• Inactivate the activator of
the prodrug
Biochemical mechanisms
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”
Mechanisms
• High-level resistance: completely resistant to any achievable concentration
• Partial resistance: small change in MIC
Mechanisms of selection
How Antimicrobial Use Increases Resistance: Mechanisms
Rx
• “Acquired” Resistance: selection within host– Patient infected with a susceptible
organism– Treatment selects a resistant variant
Emerg Inf Dis 2002 8:347
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 Rx
How Antimicrobial Use Increases Resistance: Mechanisms
• Increasing susceptibility to colonization– Patient carries a “normal flora”– Treatment increases susceptibility to
colonization by opening ecologic niche
Rx
Summary of Mechanisms of Selection of Resistance by Abx
Rx
Rx
Rx
Acquired resistance during
Tx
Primary resistance
(Infected with Res strain)
Colonization susceptibility
Examples TB, HIV, Pseudomonas
All? Most Commensals: pneumococcus,
nosocomials
Relation between selection and treatment success - + ? Relation between selection and dose/number of abx - +? +?
Is antibiotic use harmful to
individuals?
Co-selection
• Dental fillings installed and removed from experimental monkeys
Summers 1993 AAC
Concepts and questions
• Antibiotic resistance is interesting: how bad is it?
• How can we measure the costs? Compared to what?
What can we do to/for an individual patient to prevent resistant
infections?
Why have some kinds of drug resistance increased fast, others
slowly or not at all?
What can we do to the population as a whole to reduce the risk of
reistant infections?
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?
What would happen if we stopped using antibiotics tomorrow?
• To disease?
• To resistance?