La terapia delle infezioni da S. aureo “difficile”

1 La terapia delle infezioni da S. aureo difficile Prof. Ercole ConciaUniversit degli studi di VeronaVerona, 22 ottobre 2010 EVOLUTION OF RESISTANCE IN S. AUREUS1940:Benzylpenicillin (penG) introduced1948: -lactamase-positive strains predominate1950s:Resistant to all available agents1960s:Semi-synthetic penicillins introduced1961:Methicillin-resistant strains appeared1970s:Multidrug-resistant (MDR) MRSA strains detected1980s:Global spread of MDR MRSA1990s:Increasing MRSA in hospitals, sporadic nosohusial cases1997:VISA and hVISA( reduced vancomycin susceptibility)1998:CA-MRSA no link to healthcare institutions 2002.

2 VRSA (VanA)MRSA Rates are Increasing worldwideGrundmann H, et al. Lancet2006; 368:874 8501020304050607080901001999200020012002 20032004200520062007 Rate of invasive MRSA in Italy: 1999-2007 MRSA in Ospedale EARSS 2004020406080 ICUO ncologyUrologyPaediatricsObstetricsOrtho pedicsNeurosurgeryInternal in different clinical settingsMSSA (363)MRSA (199) OASIS Staphylococcus aureus: resistenze associate a MSSA e MRSAG. Gesu 2009 Mortalit per infezioni da MRSA Mortality was almost 2-fold higherfor bloodstream infections due MRSA compared to MSSA (OR = , 95% CI, , , p < ) in a recent meta-analysisCosgrove, SHEA 2001 Vancomycin MIC creep USA datanumberMIC50 MIC90N(%) MIC > (3)*2004 (100)*1985 (8)*2004 (89)** P< -Kapadia M.

3 Et al 45 ICAAC abs E-807 Moise et al AAC 2007 MIC per vancomicina e % di eradicazioneCID 2008 Mortality associated with MRSA bacteremia was significantly higher when vancomycin was used with strains with an MIC >1 mg/L Influenza della MIC di vancomicina sul trattamento di batteriemia da MRSALa MIC alla vancomicina un fattore predittivo significativo di fallimento terapeutico nelle infezioni da G, et al. J Clin Microbiol2004; 42 L, et al. Arch Intern Med2006; 166 P, et al. Clin Infect Dis2004; 38 P, et al.

4 Antimicrob Agents Chemother2007; 51:2582-2586* Valore dipnon riportato Successo definito come eradicazione alla fine del trattamentoSuccessi del trattamentocon vancomicina (%)100206040 Moise-Broder 20043*Moise 20074* 08021 Hidayat 20062 MIC alla vancomicina0,5 mg/ml 7177829521,0 mg/ml 2,0 mg/ml Successi del trattamentocon vancomicina (%)10080604020 MIC alla vancomicina0,5 mg/ml 1,0 2,0 mg/ml 0100806040200 MIC alla vancomicina 1,0 mg/ml 2,0 mg/ml Sakoulas 200418562p=0,02n=40n=39n=21n=17n=25n=14n =13n=79,5p=0,0155,6n=9n=21 Successi del trattamentocon vancomicina (%)Distribuzione MIC Vancomicina (480 ceppi di SAU)60370,472251,860381,8010203040506070 800,512 BASPEMOPUSPer Teicoplanina le MIC sono per il 99% 0,5 Verona, G.

5 LocascioAutomated system indequately capture vancomycin MICsVancomycin2481632 Vancomycin (CNS) aureuswith vancomycin MIC values of 2 mg/L are on the border of the wild type MIC distribution and may have an impaired clinical response. The I/R breakpoint was reduced to 2 mg/L to avoid reporting VISA isolates intermediate as serious infections with VISA isolates are not treatable with increased doses of vancomycin or teicoplanin. Glycopeptides - EUCAST clinical MIC breakpoints2009-05-20 (v )Vancomycin1248 Teicoplanin1248 Teicoplanin (CNS)1248 Chua and Howden Current Opinion in Inf.

6 Dis. 2009 Sakoulas and Moellering CID 2008A recent analysis of 900 bloodstream MRSA isolates from nine medical centres in the USA demonstrated tolerance to vancomycin, defined as an MBC: MIC ratio 32, in 181 isolates ( ).Nguyen HM at al. -JAC doi: 377 (2009)CMI VANCOMICINA 1 mg/ml o mancata risposta alla vancomicina qualunque sia il valore della le dosi di la i nuovi delle infezioni DA MRSACMI VANCOMICINA 1 CMI VANCOMICINA 1 VANCOMICINA TEICOPLANINABATTERIEMIESEPSIENDOCARDITIP OLMONITIINFEZIONI SNCSSSIDAPTOMICINALINEZOLID*TIGECICLINAD APTOMICINALINEZOLIDOSTEOMIELITIDAPTOMICI NA*LINEZOLID** Indicazioni off label per le osteomieliti e per le infezioni del SNCANTIBIOTICI AD ATTIVITA

7 ANTISTAFILOCOCCICAMSOXACILLINACEFAZOLINA RIFAMPICINACOTRIMOXAZOLOMRVANCOMICINATEI COPLANINAMINOCICLINACOTRIMOXAZOLOACIDO FUSIDICORIFAMPICINAMR/GISALINEZOLIDDAPTO MICINATIGECICLINADALBAVANCINACEFTOBIPROL OTELAVANCINAORITAVANCINADEFINITION OF COMMUNITY-ACQUIRED MRSA Any outpatient or inpatient with culture-confirmed MRSA infection who had no history of hospitalization, surgery, renal dialysis or residence in LTCF within 1 yearbefore MRSA culture date(Naimi T et al. CID 2001)MOLECULAR MECHANISMS OF MRSA The mecAgene is carried on theStaphylococcal Cassette Chromosome mec (SCCmec),a mobile genetic element, highly conserved, not plasmid borne.

8 SCCmecincludes also antibiotic resistance genes(to erythromycin, spectinomycin, tetracycline, kanamycin and others) and recombinase genes (ccr A and B)involved in the transfer of the SCCmec elements between strains. HA-MRSA:SCCmec types: I, II, III, IV (rare) CO-MRSA: IV, V;smaller in size, lacking any other antibiotic resistant genesVIRULENCE FACTORS OF CA-MRSA PANTON-VALENTINE LEUKOCIDIN (PVL)gene: Production of a synergohymenotropic TOXIN which damages membranes and is lytic for a wide variety of cell lines Found in 2-3%of S.

9 Aureusstrains, isolated in France Reports in USA, Switzerland, Latvia, Germany Detected in 8% of MRSA isolated in hospitalsin 2003 in the Netherlands. Associated with skin infectionsand severe necrotizing pneumonia 4 cases of severe necrotizing CAP caused by MRSA carrying the PVL genes, reported in USA (Francis JS, CID 2005) ENTEROTOXINS C and H genesCLINICAL MANIFESTATIONS (CDC)SKIN/SOFT TISSUE INFECTION1266 (77%)WOUND (traumatic)157 (10%)URINARY TRACT INFECTION64 (4%)SINUSITIS61 (4%)BACTEREMIA43 (3%)PNEUMONIA31 (2%)Low prevalence (0-5%)France 2003: PVL+ is and MRSA is 2% of all S.

10 Aureus in the community (Naas T et al, J Hosp Infect 2005;61:321-9)France: of ST80 PVL+ among 111 MRSA collected in 23 hospitals from deep seated infection in 2006-2007UK: frequency of PVL positive only of 515 MRSA sent to the National Ref Center (Holmes et al, 2005 43: 2384-2390)Medium prevalence (5-20%)Austria: in 2005 to in 2006 of MRSA were PVL positive(Krziwanek et al, Eur J Clin Microbiol Infect Dis 2007 26:931-5)Netherlands: 10% of all MRSA were PVL positive (Wannet et al, J Clin Microbiol 2005.)