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Evoluzione dell’antibiotico-resistenza: miti e realtà

Gian Maria Rossolini Dip. Biologia Molecolare Sezione di Microbiologia Università di Siena UO Microbiologia e Virologia Azienda Osp-Univ Senese. Evoluzione dell’antibiotico-resistenza: miti e realtà. Inhibition zones. How do we define resistance?. Broth or agar dilution tests.

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Evoluzione dell’antibiotico-resistenza: miti e realtà

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  1. Gian Maria Rossolini Dip. Biologia Molecolare Sezione di Microbiologia Università di Siena UO Microbiologia e Virologia Azienda Osp-Univ Senese Evoluzione dell’antibiotico-resistenza: miti e realtà .

  2. Inhibition zones How do we define resistance? Broth or agar dilution tests MIC values Interpretation of results based on clinical breakpoints

  3. The clinical breakpoints Reference MIC/zone values for interpretation of the results of in vitro susceptibility testing Definitionofsusceptibilitycategory (S/I/R) referredtoclinicaluse Clinical breakpoints are defined by specific committees

  4. Breakpointcommittees in Europe

  5. with different opinions... Kahlmeter et al – JAC 2003

  6. December 2004

  7. The EUCAST Mission • to harmonise clinical breakpoints in Europe • to determine breakpoints for new antimicrobials • to provide standardised methodology for AST

  8. Setting clinical breakpoints for new drugs in Europe Co-ordinated process between the Company, EMEA and EUCAST When a Company applies for registration of a new agent: EUCAST defines the breakpoints EMEA decides on all other aspects EUCAST breakpoints for new drugs are the only ones included in the SPC (Summary of Product Characteristics)

  9. EUCAST clinical breakpoints Freely available on the WEB Institutional decision body (industry has a consulting role but does not participate in the decisional process) Defined by consensus Rationale for decision disclosed (rationale documents available)

  10. EUCAST vs. CLSI breakpoints:a remarkable diversity Courtesy by G. Kahlmeter

  11. EUCAST vs. CLSI breakpoints: Pseudomonas aeruginosa For S: EUCAST 5/11 lower For R: EUCAST 8/11 lower

  12. EUCAST vs. CLSI breakpoints: Enterobacteriaceae(beta-lactams & quinolones) ForS: EUCAST 9/9lower ForR: EUCAST 7/9lower

  13. EUCAST vs. CLSI breakpoints: Enterobacteriaceae(other agents) For S: EUCAST 3/4 lower For R: EUCAST 3/4 lower, 1/4 higher

  14. EUCAST vs. CLSI Will the change from CLSI to EUCAST breakpoint system significantly affect the epidemiology of antibiotic resistance?

  15. EUCAST vs. CLSI • A comparative analysis of AST results interpreted according to CLSI or EUCAST • Data source: historical records from clinical microbiology service, Siena University Hospital (year 2008)

  16. Pseudomonas aeruginosaGentamicin (N = 295) EUCAST CLSI 64 2 4 8 16 32 MIC (mg/L) EUCAST: RCLSI: I

  17. Pseudomonas aeruginosaAmikacin (N = 296) EUCAST CLSI 64 2 4 8 16 32 MIC (mg/L) EUCAST: ICLSI: S EUCAST: RCLSI: I

  18. Pseudomonas aeruginosaCeftazidime (N = 294) EUCAST CLSI 32 1 2 4 8 16 MIC (mg/L) EUCAST: RCLSI: I

  19. Pseudomonas aeruginosaMeropenem (N = 216) EUCAST CLSI 64 2 4 8 16 32 MIC (mg/L) EUCAST: ICLSI: S

  20. Pseudomonas aeruginosaPip/Tazo (N = 289) EUCAST CLSI 64 2 4 8 16 32 MIC (mg/L) EUCAST: RCLSI: S

  21. Pseudomonas aeruginosaAztreonam (N = 133) EUCAST CLSI 32 1 2 4 8 16 MIC (mg/L) EUCAST: ICLSI: S

  22. Pseudomonas aeruginosaCiprofloxacin (N = 295) EUCAST CLSI 8 0.25 0.5 1 2 4 MIC (mg/L) EUCAST: ICLSI: S EUCAST: RCLSI: I

  23. Pseudomonas aeruginosaCLSI vs. EUCAST % susceptibility Antibiotics

  24. MRSAimpact(USA) a in hospital deaths Boucher & Corey Clin Infec Dis 2008

  25. Resistance trends in major pathogens Europe MRSA E. coliRto 3GC 8/30 8/30 14/30 = 23/30 1/30 6/30 = Countries 2008: 21/30 0/30 9/31 = 2008: 2/31 10/31 19/31 = EARSS annual report, 2007

  26. Resistance trends in major pathogens Europe E. coliRto 3GC 23/30 1/30 6/30 = Countries MDR E. coli (R to 3GC,AG,FQ) 24/30 0/30 6/30 = EARSS annual report, 2007

  27. The growing challenge of resistant Gram-negatives • MRSA and VRE rates have leveled off or decreasing in several European countries • Resistant Gram-negatives are increasing in most European countries • Major challenges: • Enterobacteriaceae • ESBL/AmpC, MDR, XDR (ESC/FQ/AG/NEM) • Pseudomonas aeruginosa and Acinetobacter • MDR, XDR (COL-S only) Rossolini & Mantengoli, CMI 2008

  28. ESBLs: increasing trends K. pneumoniae % resistant to 3GC Year EARSS database

  29. ESBLs: increasing trends E. coli % resistant to 3GC Year EARSS database

  30. ESBL-producing Enterobacteriaceae , Italy % Spanu et al. - AAC 2002; Luzzaro et al. - JCM 2006; OASIS study, data on file

  31. Ampicillin >128 R Amoxi/Clav 32 R Pip/Tazo 4 S Cephalotin 32 R Cefotaxime 64 R Ceftazidime 32 R Cefepime 2 Ertapenem 0.12 S Amikacin 2 S Gentamicin 4 S Ciprofloxacin >32 R Levofloxacin >32 R MIC (mg/L) 2003: Proteus mirabilis (isolates from UTIs and ulcers) Suspect ESBL Aztreonam R S Amoxi/Clav Ceftazidime Resistant to 3rd gen. ceph. but ESBL-negative Cefotaxime Ceftriaxone

  32. Same clone detected in LTCFs . By clonal expansion P. mirabilis resistant to 3rd gen. cephalosporins Luzzaro et al – IJAA 2009

  33. Clinicalfeaturesofinfectionscausedby the P. mirabilis CMY-16+ Mean age: 75±15 yrs (76±16 for ESBL+; 57±28 for susceptible strains) Female/male ratio: 1.1 (1.6 for ESBL+; 2.1 for susceptible strains) 80% 37% 51% Patients Sources Luzzaro et al – IJAA 2009

  34. 2007-2008: P. mirabilis CMY+ spreading in Italy >30 casesfromBSIs Clonally related isolates detected in Greece and Poland: an internationally spreading clone D’Andrea et al – unpublished

  35. Increased Carb-R strains Increased carbapenem use Cross transmission of Carb-R strains Selection of Carb-R strains ESBLs/AmpC and carbapenem overuse Increased # ESBL/AmpC cases

  36. Ampicillin >16 R Amoxi/Clav >16 R Pip/Tazo >64 R Cefotaxime >16 R Ceftazidime >32 R Cefepime >16 R Aztreonam >16 R Imipenem ≤1 Meropenem 2-4 Ertapenem >4 R Amikacin >32 R Gentamicin >8 R Tobramycin >8 R Ciprofloxacin >32 R Levofloxacin >32 R TMP/SXT >2 R Tigecycline 1 - 2 Colistin <1 MIC (mg/L) 2007-2008: emergence of MDR Klebsiella pneumoniae ERT-R from several hospitals … Nationwide clonal spread (ST37) No carbapenemase act. • Production of: • CTX-M-15 ESBL • SHV-11 • - (OXA-9) (TEM-1) Reducedporinexpression D’Andrea et al. – 19th ECCMID

  37. Ampicillin >16 R Amoxi/Clav >16 R Pip/Tazo >64 R Cefotaxime >16 R Ceftazidime >32 R Cefepime >16 R Aztreonam >16 R Imipenem ≤1 R Meropenem 2-4 R Ertapenem >4 R ESBL positive Amikacin >32 R Gentamicin >8 R Tobramycin >8 R Ciprofloxacin >32 R Levofloxacin >32 R TMP/SXT >2 R Tigecycline 1 - 2 S Colistin <1 MIC (mg/L) Klebsiella pneumoniae with reduced carbapenem susceptibility due to ESBL prod. + porin loss: detection and reporting issues Vitek-2 AES: changestoresistancetoall carbapenems

  38. KPC-2 K. oxytoca Yigit et al. AAC 2003

  39. Brooklyn, New York … • 22% of isolates resistant to: • Aminoglycosides • Fluoroquonolones • 3rd 4th gener. Cephems • Carbapenems Klebsiella pneumoniae Due to spread of KPC carbapenemases • Susceptibility only to: • Colistin • Tigecycline Landman et al – JAC 2007

  40. KPC-type carbapenemases in Israel: a major problem Nationwideoutbreak Carbapenem resistance rates in K. pneumoniae from Israel: 2006: 11% 2007: 22% 2008: 19% EARSS database

  41. KPC-type carbapenemases: a new pandemic? 7 cases Twocases, onewith Israel connection 4 fromGreece 2 from Israel Clonallyrelated Intercontinental spread of ST258 KPC+ clone Villegas et al. AAC 2007 Tsakris et al. JAC 2008 Clonallyrelated Literacka et al. AAC 2009 Hawser et al. IJAA 2009 Nordmann et al. Lancet ID 2009

  42. KPC-type carbapenemases: emerging in Italy • Oct 2008: KPC-3 positive K. pneumoniae ST258 isolated from a cIAI (high-level carbapenem resistance) Florence • No epidemiological link with areas of endemicity, but patient cared for by a trainee from Israel Giani et al - JCM 2009 • May 2009: KPC positive K. pneumoniae • Patient transferred from another hospital Lecco • Large outbreak ongoing in that hospital (26 patients colonized or infected), variable carbapenem resistance • Mostly by clonal spread (ST258), but at least two clones and also in Enterobacter Luzzaro et al - unpublished Santoriello et al - unpublished • Additional reports

  43. Carbapenem-resistant K. pneumoniae, Greece Production of VIM-1 MBL Multiple clones Often susceptible only to colistin and tigecycline (XDR) Vatopoulos et al. - Eurosurveillance 2008 Psichogiou et al. – JAC 2008

  44. Carbapenemases of clinical relevance KPC-type (active-site serine, class A) Metallo-β-lactamases (class B) OXA-type (active-site serine, class D)

  45. VIM-1 MBL-producingindex strain VR-143/97 (ser. O11; ST227) GM IPM VERONA 1997 FEP COL TOB TZP CAZ MEM ATM PRL AK Lauretti et al. – AAC 1999 Cornaglia et al. – CID 2000 CIP

  46. CREMONA 0.6% VARESE 2.6% TURIN 0% PERUGIA 1.1% PAVIA 1.3% L’AQUILA 0% GENOA 0% FOGGIA 1.2% ROME 0.3% AVELLINO 1.4% SASSARI 0.9% NEAPLES 9.2% Acquired MBLs in Pseudomonas aeruginosa first Italian nationwide survey 2004: Overall prevalence 1.3% 2008: Overallprevalence 7% Rossolini et al. AAC 2008 Luzzaro et al. - unpublished

  47. Conclusions • CLSI soon replaced by EUCAST: resistance rates will be affected in some cases • Resistance in Gram-negatives: now a major problem • XDR phenotypes not only in Pseudomonas and Acinetobacter but also among enterobacteria • Multiple resistance mechanisms: not easily deducible from the antibiotype • Open issues in: lab detection, reporting, infection control and treatment

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