Transcript Diapositiva 1

EMERGENZE INFETTIVE DAL 1970
It is time to “close the book
on infectious diseases.”
Surgeon General William H. Stewart
Congressional testimony
by the Surgeon General
of the United States, 1969
16 antimicrobial compounds in
late-stage clinical development
Eight compounds have activity
against gram-positive
organisms
Eight compounds have activity
against both gram-positive
and gram-negative organisms
From these 13 pharmaceutical leaders,
just 3 new compounds are in advanced
clinical development, thus reflecting the
companies’ decreased investment in
this therapeutic area
Compounds with activity against both Grampositive and Gram-negative organisms
Stage of
clinical
developement
Class
Enterob. ESBL+
Tomopenem
II
Carbapenem

PTK-0796
II
Aminomethylcycline

ME 1036
I
Carbapenem

Sulopenem
I
Carbapenem

PZ-601
II
Carbapenem

BAL 30376
I
βl/ βli
combination

ME 1071
I
Metallo βlactamase inh.
Acinetob.
MDR
P. aeruginosa
MDR
Non Imipenemresistant





Pharmacogenomics, 2008
Non-antibiotic coumpounds
Cationic Antimicrobial
peptides (CAMPs)
Part of the host immunity; promiscuous mode of action
Acyldepsipeptides
(ADEPs)
Lipoproteins; stimulation of caseinolitys protease P (ClpP)
Bacteriophages
Antibacterial activities in animals
Probiotics
Prevention of antibiotic resistance
Silver
Antimicrobial activity
Nonculturable bacteria
DNA sequences could provide hits for potential novel
antibiotics
Pharmacogenomics, 2008
Non-antibiotic coumpounds
Cationic Antimicrobial
peptides (CAMPs)
Part of the host immunity; promiscuous mode of action
Acyldepsipeptides
(ADEPs)
Lipoproteins; stimulation of caseinolitys protease P (ClpP)
Bacteriophages
Antibacterial activities in animals
Probiotics
Prevention of antibiotic resistance
Silver
Antimicrobial activity
Nonculturable bacteria
DNA sequences could provide hits for potential novel
antibiotics
1.
2.
3.
4.
5.
Hand washing
Full-barrier precautions
during catheter insertion
Cleaning the skin with
clorexidine
Avoiding femoral site if
possible
Removing unnecessary
catheters
Multifaceted interventions
Introduction of VAP bundle
Measure of compliance and feedback
Cocanour CS et al. J Trauma 2006
• Very advanced diagnostic technology..
• Very rapid turnaround time (15 min)..
• Bed-side diagnosis..
“despite the advance in diagnostic technology, it has been
necessary to maintain proficiency at the reference laboratory
in “old school” microbiology skills such as culture,
identification, and susceptibilities testing of bacteria, fungi,
parasites, and viruses”
Molecular test versus standard culture
RR (95% CI) 0.87 (0.61-1.24)
Molecular test versus no screening
Incidence of MRSA BSI
RR (95% CI) 0.54 (0.41-0.71)
Incidence of MRSA SSI
RR (95% CI) 0.69 (0.46-1.01)
Multi-drug resistant organisms control in hospital
Alert systems and IC Task Force
• Diagnosis of infection OR
colonization
• Appropriate antibiotic therapy
• Application of infection control
measures
• Education of HCWs
• Follow-up
Policlinico A. Gemelli
114 Alerted case from May to October 2009
MDR Acinetobacter spp
56
MRSA
29
MDR P. aeruginosa
17
VRE
6
ESBL-producing gram negative
4
S. maltophilia
2
49% from medicine wards
20% from ICU
18% from surgery
13% from rehabilitation and geriatrics
HIV
Factors Affecting Concentration of
Antiviral Drug at its Site of Action
Absorption
Oral
Administration
Metabolism
CYPs
P-gp
Dissolution
LIVER
GI MUCOSA
Drug
(tablet/capsule)
SYSTEMIC
CIRCULATION
Protein
Bound
Drug
Free
Drug
PIs
NNRTIs
CYP3A4/5
CYP2B6
CYP2C19
P-gp
Distribution
TISSUES
Excretion
TARGET CELL
• NRTIs
Bound Drug
(Intracellular Phosphorylation)
URINE
Free Drug
NRTIs
• Protease Inhibitors
• NNRTIs
TDM
Toxicity
Efficacy
Predictors of
48 weeks virological failure
Univariate analysis
HR (95% CI)
0.78 (0.62-0.98)
0.031
Multivariate analysis
HR (95% CI)
0.70 (0.53-0.94)
0.016
Non-italian born
1.74 (1.06-2.83)
0.027
2.81 (0.90-8.75)
0.075
Injecting drug users
1.55 (1.02-2.35)
0.040
1.78 (0.93-3.43)
0.084
Past AIDS defining events
1.88 (1.27-2.78)
0.002
2.25 (1.59-3.76)
<0.001
Past suboptimal therapy
1.61 (1.09-2.39)
0.017
1.43 (0.79-2.57)
0.234
Treatment line (per 1 line more)
1.31 (1.08-1.58)
0.007
1.13 (0.89-1.45)
0.315
Baseline viral load (per 1 log more)
2.24 (1.93-2.60)
<0.001
2.10 (1.67-2.64)
<0.001
Baseline CD4 (per 100 cells more)
0.88 (0.82-0.96)
0.003
0.97 (0.89-1.05)
0.446
Therapeutic drug levels
0.46 (0.30-0.71)
<0.001
0.47 (0.29-0.79)
0.004
Age (per 10 years more)
p
p
Therapeutic drug levels independently associated with a lower
risk of virological failure
Fabbiani M. et al. JAC 2009
The 50 Best Inventions of 2009
From a rocket of the future to a $10 million lightbulb, here are TIME's picks for the best new
gadgets and breakthrough ideas of the year
Lights and shadows of clinical trials of HIV vaccines
• The first three Phase III clinical trials have been discontinued for safety reasons, having more
infections among the vaccinated than the placebo group.
• Recently the Phase III clinical trial performed in Thailand using a priming with recombinant
canarypox vector (ALVAC-HIV) plus two booster injections of a recombinant glycoprotein 120
subunit vaccine (AIDSVAX B/E) showed a 30% reduced infections in the vaccinated group.
Published on October 20, 2009 N Engl J Med 2009;361.
Our “shock and kill” technique
uninfected cells
infected cells
high
“Shock”
intracellular
glutathione
levels
Addition of an HDAC inhibitor
low
“Kill”
Addition of buthionine sulfoximine
Cells survive treatment
Cells die
Scaffold
Medicine
Diversity-Oriented Synthesis: un
approccio alla diversità strutturale
Molecular modeling preliminare
HLA B*5701
e
Abacavir
CYP2B6
e
Efavirenz
HLA, CYP2B6,
ABCB1
e
NEVIRAPINA
UGT1A1
e
Atazanavir
Individualized Medicine
INTELLIGENT
TECHNOLOGY
Interventional trial
TREAT wards vs controls
Treatment costs
800
Euros
700
P = 0.007
600
500
400
300
200
100
0
IL-ctrl
IL-TREAT
Direct
G-ctrl
G-TREAT
Side effects
IT-ctrl
IT-TREAT
Resistance
Controls
Total costs
TREAT
Hematological
analysis
Microbiological
analysis
All laboratories analysis of all
patients of the hospital are
stored into
the central
database.
Periodically
a
procedure extracts analysis for
all patients present in the
database server and stores
them into a shared directory
on the server machine.
Physicians’ home
Chemical analysis
An
Open
Source
ETL
(Extraction
Transformation and Load) tool is installed
server-side. An automated process extracts
analysis from the shared directory, applies
several transformations in order to make
analysis fit physicians’ needs and stores them
into the analysis table.
The chemical analysis mask, with
de-normalized data (one exam = one column)
ETL tool loads data into a relational database, built with normalized
structure and exposed on Internet/intranet via secure ODBC connection.
Analysis structure is de-normalized in real-time during physicians db
exploration and is shown in user friendly forms. User authentication
provides access control and strict db privileges management.
…read/write…
Virolab offices
Results: GRT vs. DH
by therapy line
There is an increase in performance
by increasing the therapy line: i.e. all
models predict better when there is a
long known therapy history
On the other hand, subsequent
therapy lines are likely to be more
unsuccessful
failure
success
100%
80%
60%
40%
20%
0%
p<0.0001
first
second
third
fourth or
more
653
337
299
1542
therapy line
HEALTH
TECHNOLOGY
ASSESSEMENT