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Congressional testimonyCongressional testimonyby the Surgeon Generalby the Surgeon General
of the United States, 1969of the United States, 1969
It is time to “close the bookIt is time to “close the bookon infectious diseases.”on infectious diseases.”
EMERGENZE INFETTIVE DAL 1970EMERGENZE INFETTIVE DAL 1970
Surgeon General William H. Stewart
16 antimicrobial compounds in 16 antimicrobial compounds in late-stage clinical developmentlate-stage clinical development
Eight compounds have activity Eight compounds have activity against both gram-positive against both gram-positive
and and gram-negative organismsorganisms
Eight compounds have activity Eight compounds have activity against gram-positive against gram-positive
organismsorganisms
From these 13 pharmaceutical leaders, just 3 new compounds are in advanced clinical development, thus reflecting the companies’ decreased investment in this therapeutic area
Stage of Stage of clinical clinical
developement developement ClassClass Enterob. ESBL+
Acinetob.
MDR
P. aeruginosa
MDR
Tomopenem II Carbapenem Non Imipenem-resistant
PTK-0796 II Amino-
methylcycline
ME 1036 I Carbapenem
Sulopenem I Carbapenem
PZ-601 II Carbapenem
BAL 30376 I ββl/ l/ ββli li combinationcombination
ME 1071 IMetallo ββ--
lactamase inh.lactamase inh.
Compounds with activity against both Gram-Compounds with activity against both Gram-positive and positive and Gram-negative organismsorganisms
Pharmacogenomics, 2008Pharmacogenomics, 2008
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 bacteriaDNA sequences could provide hits for potential novel antibiotics
Non-antibiotic coumpoundsNon-antibiotic coumpounds
Pharmacogenomics, 2008Pharmacogenomics, 2008
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 bacteriaDNA sequences could provide hits for potential novel antibiotics
Non-antibiotic coumpoundsNon-antibiotic coumpounds
1. Hand washing2. Full-barrier precautions
during catheter insertion3. Cleaning the skin with
clorexidine4. Avoiding femoral site if
possible5. Removing unnecessary
catheters
Multifaceted interventions
Cocanour CS et al. J Trauma 2006
Introduction of VAP bundleMeasure of compliance and feedback
• 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”
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)
Molecular test versus no screening
Multi-drug resistant organisms control in hospitalMulti-drug resistant organisms control in hospitalAlert systems and IC Task ForceAlert 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
MDR Acinetobacter spp 56
MRSA 29
MDR P. aeruginosa 17
VRE 6
ESBL-producing gram negative 4
S. maltophilia 2
114 Alerted case from May to October 2009
49% from medicine wards20% from ICU18% from surgery13% from rehabilitation and geriatrics
TISSUESBound Drug
Free Drug
URINENRTIs
Dissolution
Absorption
Distribution
Excretion
SYSTEMIC CIRCULATION
FreeDrug
ProteinBoundDrug
Metabolism
TARGET CELL• NRTIs
(Intracellular Phosphorylation)
• Protease Inhibitors• NNRTIs
LIVEROral
AdministrationDrug
(tablet/capsule)
GI MUCOSA
CYPsP-gp
CYP3A4/5CYP2B6
CYP2C19P-gpPIs
NNRTIs
Factors Affecting Concentration of Antiviral Drug at its Site of Action
Predictors of 48 weeks virological failure
Univariate analysis HR (95% CI)
pMultivariate analysis
HR (95% CI)p
Age (per 10 years more) 0.78 (0.62-0.98) 0.031 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
Fabbiani M. et al. JAC 2009
Therapeutic drug levels independently associated with a lower risk of virological failure
The 50 Best The 50 Best Inventions of 2009Inventions 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.
• 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
Addition of an HDAC inhibitor
Addition of buthionine sulfoximine
Cells survive treatment Cells die
“Shock”
“Kill”
intracellularglutathionelevels
high
low
Diversity-Oriented Synthesis: un approccio alla diversità strutturale
decorazione dello scaffold
2a generazione1a generazione
B
A
C
Derivati di ammonoacidi e
zuccheri (precursori
aciclici altamente
funzionalizzati)B
C
A
C
BA
Euros
Interventional trialTREAT wards vs controlsTreatment costs
0
100
200
300
400
500
600
700
800
I L-ctrl I L-TREAT G-ctrl G-TREAT I T-ctrl I T-TREAT Controls TREAT
Direct Side eff ects Resistance Total costs
P = 0.007
Microbiological Microbiological analysisanalysis
Chemical analysisChemical analysis
Hematological Hematological analysisanalysis
An Open Source ETL (An Open Source ETL (Extraction Extraction Transformation and LoadTransformation and Load) tool is installed ) tool is installed server-side. An automated process extracts server-side. An automated process extracts analysis from the shared directory, applies analysis from the shared directory, applies several transformations in order to make several transformations in order to make analysis fit physicians’ needs and stores them analysis fit physicians’ needs and stores them into the analysis table.into the analysis table.
ETL tool loads data into a relational database, built with normalized ETL tool loads data into a relational database, built with normalized structure and exposed on Internet/intranet via secure ODBC connection. structure and exposed on Internet/intranet via secure ODBC connection. Analysis structure is de-normalized in real-time during physicians db Analysis structure is de-normalized in real-time during physicians db exploration and is shown in user friendly forms. User authentication exploration and is shown in user friendly forms. User authentication provides access control and strict db privileges management.provides access control and strict db privileges management.
……read/write…read/write…
Virolab officesVirolab officesPhysicians’ homePhysicians’ home
All laboratories analysis of all All laboratories analysis of all patients of the hospital are patients of the hospital are stored into the central stored into the central database. Periodically a database. Periodically a procedure extracts analysis for procedure extracts analysis for all patients present in the all patients present in the database server and stores database server and stores them into a shared directory them into a shared directory on the server machine.on the server machine.
The chemical analysis mask, withThe chemical analysis mask, withde-normalized data (one exam = one column)de-normalized data (one exam = one column)
Results: GRT vs. DHResults: GRT vs. DHby therapy lineby therapy line
0%
20%
40%
60%
80%
100%
first second third fourth ormore
653 337 299 1542
p<0.0001 therapy line
failure success
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