Evoluzione dellantibiotico-resistenza: miti e realt
Gian Maria Rossolini Dip. Biologia Molecolare Sezione di Microbiologia Universit di Siena UO Microbiologia e Virologia Azienda Osp-Univ Senese MIC values Inhibition zones Broth or agar dilution tests How do we define resistance? Interpretation of results based on clinical breakpoints Reference MIC/zone values for interpretation of the results of in vitro susceptibility testing The clinical breakpoints Definition of susceptibility category (S/I/R) referred to clinical use Clinical breakpoints are defined by specific committees Breakpoint committees in Europe Committee Country BSAC United Kingdom CA-SFM France CRG The Netherlands DIN Germany NWGA Norway SRGA Sweden CLSI USA Enterics / cefotaxime S< / R> BSAC United Kingdom 1 / 1 CA-SFM France 4 / 32 CRG The Netherlands 4 / 8 DIN Germany 2 / 8 CLSI U.S.A. 8 / 32 NWGA Norway 1 / 2 SRGA Sweden 0.5 / 1 with different opinions... Kahlmeter et al JAC 2003 December 2004 to harmonise clinical breakpoints in Europe to determine breakpoints for new antimicrobials to provide standardised methodology for AST 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) EUCAST clinical breakpoints Freely available on the WEB Defined by consensus Institutional decision body (industry has a consulting role but does not participate in the decisional process) Rationale for decision disclosed (rationale documents available) EUCAST vs. CLSI breakpoints: a remarkable diversity Courtesy by G. Kahlmeter EUCAST CLSI S R> S R> Cefepime 8 8 8 16 Ceftazidime 8 8 8 16 Imipenem 4 8 4 8 Meropenem 2 8 4 8 Pip/Tazo 16 16 64 64 Aztreonam 1 16 8 16 Ciprofloxacin 0.5 1 1 2 Gentamicin 4 4 4 8 Tobramycin 4 4 4 8 Amikacin 8 16 16 32 Colistin 2 2 2 4 EUCAST vs. CLSI breakpoints: Pseudomonas aeruginosa For S: EUCAST 5/11 lower For R: EUCAST 8/11 lower EUCAST vs. CLSI breakpoints: Enterobacteriaceae (beta-lactams & quinolones) EUCAST CLSI S R> S R> Cefepime 1 8 8 16 Ceftriaxone 1 2 8 32 Ceftazidime 1 8 8 16 Ertapenem 0.5 1 2 4 Imipenem 2 8 4 8 Meropenem 2 8 4 8 Pip/Tazo 8 16 16 64 Levofloxacin 1 2 2 4 Ciprofloxacin 0.5 1 1 2 For S: EUCAST 9/9 lower For R: EUCAST 7/9 lower EUCAST CLSI S R> S R> Amikacin 8 16 16 32 Gentamicin 2 4 4 8 Tobramycin 2 4 4 8 Cotrimoxazole 2 4 2 2 Colistin 2 2 NA NA Tigecycline 1 2 NA NA For S: EUCAST 3/4 lower For R: EUCAST 3/4 lower, 1/4 higher EUCAST vs. CLSI breakpoints: Enterobacteriaceae (other agents) EUCAST vs. CLSI Will the change from CLSI to EUCAST breakpoint system significantly affect the epidemiology of antibiotic resistance? 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) Pseudomonas aeruginosa Gentamicin (N = 295) 2 4 8 16 32 64 EUCAST CLSI MIC (mg/L) EUCAST: R CLSI: I Pseudomonas aeruginosa Amikacin (N = 296) 2 4 8 16 32 64 EUCAST CLSI MIC (mg/L) EUCAST: R CLSI: I EUCAST: I CLSI: S Pseudomonas aeruginosa Ceftazidime (N = 294) 1 2 4 8 16 32 EUCAST CLSI MIC (mg/L) EUCAST: R CLSI: I Pseudomonas aeruginosa Meropenem (N = 216) 2 4 8 16 32 64 EUCAST CLSI MIC (mg/L) EUCAST: I CLSI: S Pseudomonas aeruginosa Pip/Tazo (N = 289) 2 4 8 16 32 64 EUCAST CLSI MIC (mg/L) EUCAST: R CLSI: S Pseudomonas aeruginosa Aztreonam (N = 133) 1 2 4 8 16 32 EUCAST CLSI MIC (mg/L) EUCAST: I CLSI: S Pseudomonas aeruginosa Ciprofloxacin (N = 295) 0.25 0.5 1 2 4 8 EUCAST CLSI MIC (mg/L) EUCAST: R CLSI: I EUCAST: I CLSI: S Pseudomonas aeruginosa CLSI vs. EUCAST %
s u s c e p t i b i l i t y
Antibiotics MRSA impact (USA) Boucher & Corey Clin Infec Dis 2008 a in hospital deaths Resistance trends in major pathogens Europe EARSS annual report, 2007 MRSA C o u n t r i e s
8/30 8/30 14/30 = E. coli R to 3GC 23/30 1/30 6/30 = 2008: 2/31 10/31 19/31 = 2008: 21/30 0/30 9/31 = Resistance trends in major pathogens Europe EARSS annual report, 2007 MDR E. coli (R to 3GC,AG,FQ) 24/30 0/30 6/30 = C o u n t r i e s
E. coli R to 3GC 23/30 1/30 6/30 = 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
Rossolini & Mantengoli, CMI 2008 Major challenges: Enterobacteriaceae ESBL/AmpC, MDR, XDR (ESC/FQ/AG/NEM) Pseudomonas aeruginosa and Acinetobacter MDR, XDR (COL-S only) EARSS database Year %
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K. pneumoniae ESBLs: increasing trends EARSS database Year %
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E. coli ESBLs: increasing trends % Spanu et al. - AAC 2002; Luzzaro et al. - JCM 2006; OASIS study, data on file ESBL-producing Enterobacteriaceae , Italy Suspect ESBL 2003: Proteus mirabilis (isolates from UTIs and ulcers) Aztreonam Ceftazidime Cefotaxime Ceftriaxone Amoxi/Clav Resistant to 3rd gen. ceph. but ESBL-negative 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) R S . P. mirabilis resistant to 3rd gen. cephalosporins Luzzaro et al IJAA 2009 Same clone detected in LTCFs By clonal expansion Luzzaro et al IJAA 2009 Clinical features of infections caused by the P. mirabilis CMY-16+ Mean age: 7515 yrs (7616 for ESBL+; 5728 for susceptible strains)
Female/male ratio: 1.1 (1.6 for ESBL+; 2.1 for susceptible strains) Inpatients LTCFs HCAss CA 51% 37% Patients UTIs LRTIs SSSIs BSIs 80% Sources 2007-2008: P. mirabilis CMY+ spreading in Italy Clonally related isolates detected in Greece and Poland: an internationally spreading clone DAndrea et al unpublished >30 cases from BSIs Courtesy of Vincent Jarlier, Sept 2009 (modified) ESBLs/AmpC and carbapenem overuse Increased # ESBL/AmpC cases Increased Carb-R strains Cross transmission of Carb-R strains Selection of Carb-R strains
Increased carbapenem use Production of: - CTX-M-15 ESBL - SHV-11 - (OXA-9) (TEM-1) DAndrea et al. 19th ECCMID 2007-2008: emergence of MDR Klebsiella pneumoniae ERT-R from several hospitals 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) Reduced porin expression No carbapenemase act. Nationwide clonal spread (ST37) 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: changes to resistance to all carbapenems KPC-2 K. oxytoca Yigit et al. AAC 2003 22% of isolates resistant to: - Aminoglycosides - Fluoroquonolones - 3rd 4th gener. Cephems - Carbapenems Klebsiella pneumoniae Susceptibility only to: - Colistin - Tigecycline Due to spread of KPC carbapenemases Brooklyn, New York Landman et al JAC 2007 KPC-type carbapenemases in Israel: a major problem Nationwide outbreak Carbapenem resistance rates in K. pneumoniae from Israel: 2006: 11% 2007: 22% 2008: 19% EARSS database KPC-type carbapenemases: a new pandemic? Two cases, one with Israel connection Clonally related 7 cases 4 from Greece 2 from Israel Clonally related Nordmann et al. Lancet ID 2009 Villegas et al. AAC 2007 Tsakris et al. JAC 2008 Hawser et al. IJAA 2009 Literacka et al. AAC 2009 Intercontinental spread of ST258 KPC+ clone KPC-type carbapenemases: emerging in Italy Giani et al - JCM 2009 Florence Oct 2008: KPC-3 positive K. pneumoniae ST258 isolated from a cIAI (high-level carbapenem resistance) No epidemiological link with areas of endemicity, but patient cared for by a trainee from Israel Lecco May 2009: KPC positive K. pneumoniae Patient transferred from another hospital Large outbreak ongoing in that hospital (26 patients colonized or infected), variable carbapenem resistance Luzzaro et al - unpublished Santoriello et al - unpublished Mostly by clonal spread (ST258), but at least two clones and also in Enterobacter Additional reports 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 KPC-type (active-site serine, class A) OXA-type (active-site serine, class D) Metallo--lactamases (class B) Carbapenemases of clinical relevance GM COL AK TOB FEP IPM MEM CAZ TZP ATM CIP PRL Lauretti et al. AAC 1999 Cornaglia et al. CID 2000 VERONA 1997 VIM-1 MBL-producing index strain VR-143/97 (ser. O11; ST227) Acquired MBLs in Pseudomonas aeruginosa first Italian nationwide survey VARESE 2.6% PAVIA 1.3% CREMONA 0.6% PERUGIA 1.1% SASSARI 0.9% ROME 0.3% AVELLINO 1.4% NEAPLES 9.2% FOGGIA 1.2% GENOA 0% TURIN 0% LAQUILA 0% 2004: Overall prevalence 1.3% Rossolini et al. AAC 2008 2008: Overall prevalence 7% Luzzaro et al. - unpublished 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 Conclusions
