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”

Molecular test versus standard culture

RR (95% CI) 0.87 (0.61-1.24)

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

HIV

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

ToxicityToxicity

EfficacyEfficacy

TDM

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

Scaffold Scaffold MedicineMedicine

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

Molecular modeling preliminare

HLA B*5701 HLA B*5701 e e

AbacavirAbacavir

CYP2B6CYP2B6e e

EfavirenzEfavirenz

HLA, CYP2B6, HLA, CYP2B6, ABCB1 ABCB1

e e NEVIRAPINANEVIRAPINA

UGT1A1UGT1A1e e

AtazanavirAtazanavir

Individualized MedicineIndividualized Medicine

INTELLIGENT TECHNOLOGY

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

HEALTHTECHNOLOGYASSESSEMENT