Interindividual variability in anti-infective therapy

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Feb 21, 2013 (4 years and 4 months ago)

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Interindividual
variability in anti
-
infective therapy

Side

of

P
ersonalized Medicine



Juhee Lee


Dec 11 2006


Outline


Anti
-
infective therapy


Antibiotics


Drug resistance


Bacterial genotyping and polymorphism


Personalized antibiotics

What is infection?


De
trimental colonization of a human or animal body
by a foreign species


T
ypes of infection
:

1. Bacterial infection


T
uberculosis
(TB),
S
almonellosis
, anthrax, bacterial meningitis,
brucellosis, campylobacteriosis

2. Viral infection


AIDS,
Hepatitis B Virus ( HBV
),
Human Immunodeficiency Virus (HIV)
, common cold

3. Parasitic infection
-

amebiasis

4. Fungal infection
-

aspegillosis

5. Prion infection
-

transmissible spongiform
encephalopathy


RC Moellering,
Principles of infectious diseases
,

5th ed (2000) NY : Churchill living stone.


I
nfectious disease process

©2000 by the Regents of the U of Minnesota and

the Department of Environmental Health and Safety.

"I will lift up mine eyes to the pills."

Malcolm Muggeridge describing the age of
modern medicine in a 1962 newspaper column

Penicillin

Streptomycin

Chloroquine

Vaccine

Latex Condom

Antibiotics

World Health Organization/CDS

World Health Organization/CDS

MRSA VISA

Antibiotic resistance contributes to $4 billion

in excess avoidable healthcare costs each year.

Antibiotics Resistance

MDR
-
TB

(>2000$)

Regular
-
TB (20$)

Cost of treating MDR
-
TB

Farmer et al.
The global impact of

drug resistant TB,
Harvard medical school


and open society institute (1999) 168

Cost of MDR

It’s cheaper to treat patients

right the first time!!

DNA mutation


transformation

P
lasmid

resistance

Antibiotic resistance mechanism

Ricki Lewis
,

FDA consumer
(1995) 29

Levy, SB.
Sci Am
.
(
1998
)
46
-
53.

David C.H.
Clinical Infectious Diseases

31 (
2000
)
S24

8

Resistance mechanism to fluoroquinolones

Fluoroquinolone resistance

Erythromycin

Inhibit protein
synthesis

Point mutation of
23S rRNA

Ciprofloxacin

Inhibit DNA
replication

Point mutation in
gyrA

Campylobacter

www.jifsan.umd.edu/rps_2004.htm


Campylobacter

strains


1.
D
iverse efflux pump gene
profiles

to antibiotics resistance


2.
Single point mutation (Thr
-
86
-
Ile)
in
gyrA


caused resistance to
fluoroquinolones


:
These two mechanisms interplay
in contributing to antimicrobial
resistance of
Campylobacter

species

gyrA polymorphism in
Campylobacter

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
,
46 (
2002
)

2644

2647

SSCP patterns and QRDRs of gyrA of Campylobacter isolates

Geographical distribution of the SSCP patterns of gyrA of Campylobacter isolates


pathmicro.med.sc.edu/mayer/antibiot.htm


A MANUAL FOR MEDICAL AND

VETERINARY LABORATORIES 2006

Bacterial identification procedures

Isolation from clinical samples, Susceptibility testing, Polymorphism analysis

Identification of antibiotic resistance genes by PCR (Genotyping)

Nature Biotechnology


21
, 1233
-

1237 (2003)

Genotyping analysis by PCR

PCR

PCR

First Cycle

Second Cycle

Nature Biotechnology


21
, 1233
-

1237 (2003)

Genotyping analysis by PCR

Pseudomonas aeruginosa

Nature

406 (2000) 959
-
964

www.cellsalive.com

-
V
ersatile Gram
-
negative bacterium

-
grows in soil, marshes,


coastal marine habitats,



plant and animal tissues

-
6.3 million bp

-
Largest bacterial genome sequenced

-
Insights into intrinsic drug resistance

-
Large size and complexity


: an evolutionary adaptation


: resistance to antimicrobial substances

β−
Lactamases inactivate penicillin by opening the ring structure using water

© Health Protection Agency

H
2
O

Active

Inactive

Penicillin Resistance

JOURNAL OF CLINICAL MICROBIOLOGY
,
40(
2002
)

2420

2424

Distribution of genotypes among
P.
aeruginosa
isolates by antimicrobial
resistance

patterns. R10, isolates

coresistant to 10 antimicrobial agents

Genotype of MDR
P. aeruginosa

G
enotype

A

PNAS

99 (
2002
)

12391

12396

Streptococcus agalactiae

Phenotypes of erythromycin
-
resistant
S. agalactiae
isolates.

P1, cMLS phenotype; P2 and P3, iMLS

phenotypes; P4, M phenotype.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
,
49 (
2005
)
3080

3082

Heterogeneity of
g
enotype
-

p
henotype
c
orrelation


Clin Microbiol Infect


12 (
2006
)

1039

1042

Helicobacter pylori

-
Patients and bacterial strains.

-
Antimicrobial susceptibility testing.

-
PCR and restriction fragment length



polymorphism analysis.

-
Prevalence of antibiotic resistance


and MICs.

-
Clinical outcome.

-
Detection of gene mutations.

J
.
OF CLINICAL MICROBIOLOGY
,
40 (
2002
)
, 649

653

Antibiotic Resistance of

Helicobacter pylori

Restriction endonuclease analysis of 23S rRNA amplicons.

Digestion with
Bsa
I

Digestion with
Mbo
II

CYP2C19 pharmacogenetic polymorphism


Genotypes of CYP2C19 :

RM
-
rapid extensive metabolizer (low PPI)

IM
-
intermediate metabolizer (int PPI)

PM
-
poor metabolizer (high PPI)

Drug

M
eta
b
. Pharmacokinet.


20 (
200
5)

1
5
3

1
67

H. Pylori

eradication rates by

PPI/antibiotics therapy for the different

CYP2C19 genotype groups.

Peggy S McKinnon,

Pharmacoeconomic considerations in antibiotic selection

Strategies to reduce the costs

of antibiotic therapy

Peggy S McKinnon,

Pharmacoeconomic considerations in antibiotic selection

Cost analysis of drug resistance

Relationship between antibiotic use,
resistance, treatment failure and


healthcare burden.

Pharmacoeconomic assessment

of
antibiotic

therapy

Cost for each agent = end cost x probability (
p
) of achieving outcome

Pharmacogenomics


Pharmacogenomics
c
ould
r
eplace 'Trial
-
and
-
Error'
w
ith
s
cience
f
rom
g
enome
project.



Pharmacogenomics has the potential to

revolutionize the

prevention, diagnosis,

and
treatment of infectious diseases.



Genomics in Drug Target Identification



Based on Genome Project
,


Identify genes to pathogenic organisms


BROAD
-
> NARROW antibiotics spectrum!




Am J Health
-
Syst Pharm
.
59 (
2002
)
1626
-
31

REBUTTAL

DNA microarrays for

host
-
microbe interactions

Emerging Infectious Diseases

6 (2000) 513
-
525


Bacteria are cleverer than men!


Neu HC.
Science

257
(1992)
1064
-
1072


A normal human being hosts about 1.2 kg of bacteria


Bocci V.
Persp Biol Med

35 (1992) 251
-
260


The vision of pharmacogenomics is leading us to

a more individualized approach to the treatment

of disease in broad patient populations.

AAPS PharmSci

2 (2000) Article 4


B
io
-
terrorism prevention

http://www.lss.supelec.fr/Internet_php/pdf


P
ersonalized antibiotics


H
ybridisation bio
-
arrays

L
aboratory on chip



Personalized antibiotics

Thank you~!!