Tubercolosi Tubercolosi farmacoresistente farmacoresistente e e nuove nuove prospettive di ricerca terapeuticaprospettive di ricerca terapeutica

Lanfranco FattoriniLanfranco FattoriniIstituto Superiore di SanitàIstituto Superiore di Sanità

TB, HIV e migrazione: una reale emergenza ? TB, HIV e migrazione: una reale emergenza ? Roma, 19 maggio 2011Roma, 19 maggio 2011

TB in TB in ItalyItaly, 1955-2008, 1955-2008

Ministry Ministry of of HealthHealth, 2009, 2009

Second-lineSecond-line

FluoroquinolonesFluoroquinolones

KanamycinKanamycin

AmikacinAmikacin

CapreomycinCapreomycin

EtionamideEtionamide

PASPAS

CicloserineCicloserine

LinezolidLinezolid

First-lineFirst-line

IsoniazidIsoniazid

RifampinRifampinPyrazinamidePyrazinamide

EthambutolEthambutol

StreptomycinStreptomycin

Anti-TB Anti-TB drugsdrugs

MDRMDRXDR

Drug resistance surveillanceDrug resistance surveillance(TB-CCM Project, (TB-CCM Project, MoHMoH))

1. Proficiency testing 11. Proficiency testing 1stst + 2+ 2ndnd line drugsline drugs

2. DR data sent to 2. DR data sent to MoH MoH + ECDC, 2006-2010+ ECDC, 2006-2010

3. Microbiological studies3. Microbiological studies

TB-CCM Study Group: 32 laboratoriesTB-CCM Study Group: 32 laboratories

Peripheral labsPeripheral labs ISS (ISS (WHO SRL lab)WHO SRL lab)

First-line drug PT, 1998-2010First-line drug PT, 1998-2010

EfficiencyEfficiencyCorrect resultsCorrect results

total resultstotal results

Second-line drug PT, 2010 (13 labs)Second-line drug PT, 2010 (13 labs)

EfficiencyEfficiency

KM = kanamycin; AK = amikacin; CP = capreomycin; OFL = ofloxacin

Antibiograms Antibiograms sent to ISSsent to ISS

*

* * 2511 / 3877 2511 / 3877 notifications notifications = 65%= 65%

2009: TB in immigrants2009: TB in immigrants(14 / 75 (14 / 75 countriescountries))

(*) 2008: 53 countries(*) 2008: 53 countries

MDR-TB & immigrationMDR-TB & immigration

Ma Z, Lancet 2010Ma Z, Lancet 2010

Drugs for TBDrugs for TB

INHINH

PZAPZA

RIFRIF

Iseman Iseman M. A clinical Guide to TB, 2000M. A clinical Guide to TB, 2000

RIF+INHRIF+INH

2 4

Therapy Therapy of of active active TBTBRIF + INH + PZA + EMBRIF + INH + PZA + EMB

2 x 102 x 1099 latent latent TBTB((dormant Mtbdormant Mtb))

101077 active active TB / yTB / y

( (aerobic Mtbaerobic Mtb))

Active Active TBTB((aerobic Mtbaerobic Mtb))

Latent Latent TB TB ((dormant Mtbdormant Mtb))

Aerobic and hypoxic (dormant) Aerobic and hypoxic (dormant) MtbMtb

AEROBICAEROBIC

HYPOXICHYPOXIC

Wayne tube

AEROBIC (A)AEROBIC (A)

HYPOXIC (H)HYPOXIC (H)A5A5 H5H5

H19H19H12H12

Drug testing in the Wayne tubeDrug testing in the Wayne tube

A5A5 H19H19H12H12H5H5

In vitro activity of drugs against dormant In vitro activity of drugs against dormant MtbMtb

Activity of R-MX and R-MZ in hypoxiaActivity of R-MX and R-MZ in hypoxia

((PersistersPersisters))

R = R = rifampinrifampin; MX = ; MX = moxifloxacinmoxifloxacin; MZ = ; MZ = metronidazolemetronidazole

Activity of R-MX-AK-MZ in hypoxiaActivity of R-MX-AK-MZ in hypoxia

((PersistersPersisters))

R = R = rifampinrifampin; MX = ; MX = moxifloxacinmoxifloxacin; MZ = ; MZ = metronidazolemetronidazole; AK = ; AK = amikacinamikacin

StopLatent StopLatent TBTB

P. del Portillo(Bf7) COLOMBIA

J. Gonzalez-y-Merchand(Bf6) MEXICO

A. Coates(Bf5) UNITED KINGDOM

O. Neyrolles(Bf8) FRANCE

L. Fattorini(Bf2) ITALY

M.J. Garcia(Bf1) SPAIN(co-ordinator)

P-J. Cardona(Bf4) SPAIN

http://www.latentuberculosis.com

1.1.   The The quality quality of of Mtb drug susceptibility testing Mtb drug susceptibility testing in in Italy is Italy is accurateaccurate

2.2. 90% of new MDR-TB 90% of new MDR-TB cases were from young immigrantscases were from young immigrants, , particularly from particularly from

          former former Soviet Union Soviet Union countries countries (Romania, (Romania, UkraineUkraine, , MoldovaMoldova), China.), China.

3.3. In 66 MDR-TB In 66 MDR-TB strainsstrains, , linezolidlinezolid, , capreomycin capreomycin and and moxifloxacin were quitemoxifloxacin were quite

          activeactive; ; linezolid was active against all linezolid was active against all 5 XDR 5 XDR strainsstrains..

4.4. R-MX-AK-MZ R-MX-AK-MZ killed both aerobic killed both aerobic and and hypoxic Mtb hypoxic Mtb in vitroin vitro

5.5.    The The nitro-compounds nitro-compounds PA-824 and ND-6016PA-824 and ND-6016 are are promising drugs promising drugs

          for their activity against acidic aerobic for their activity against acidic aerobic + + hypoxic Mtbhypoxic Mtb

ConclusionsConclusions

CollaboratorsCollaborators

ISS ISS

Alessandro Alessandro MustazzoluMustazzolu Giovanni Giovanni PiccaroPiccaro Perla Filippini Perla Filippini Federico Federico GiannoniGiannoni

San San Raffaele Raffaele InstituteInstituteDaniela Daniela CirilloCirillo

The 32 labs of the TB-CCM The 32 labs of the TB-CCMStudy GroupStudy Group

StopLatent-TB StopLatent-TB