Le infezioni da patogeni multi-resistenti D.Venuti S.C. Ortopedia OEI Voltri Si possono individuare tre strategie con cui i batteri esprimono resistenza agli antibiotici modificazione del bersaglio d’azione ’ inattivazione dell’antibiotico alterazioni della permeabilità di membrana Risk Factors for Health Care-Associated Infections and Infection with Drug-Resistant Bacteria Peleg A and Hooper D. N Engl J Med 2010;362:1804-1813 Antibiotic options decline: 10 x '20 Initiative http://www.idsociety.org/badbugsnodrugs.html; last access Feb 12, 2010 Di chi preoccuparsi? Di chi preoccuparsi? MRSA Enterobatteriacee con ESBL Enterobatteriacee non suscettibili ai Carbapenemici Pseudomonas multiresistenti Acinetobacter baumanii multiresistenti Enterococchi vancomicina resistenti Pneumococchi penicillino resistenti? Stafilococco Aureo Meticillino Resistente MRSA MRSA Rates are Increasing worldwide Verona 19-01-2013 Grundmann H, et al. Lancet 2006; 368:874– 368:874–85 Verona 19-01-2013 ANTIBIOTICI AD ATTIVITA’ ANTISTAFILOCOCCICA MS MR OXACILLINA VANCOMICINA CEFAZOLINA TEICOPLANINA RIFAMPICINA COTRIMOXAZOLO MR/GISA LINEZOLID DAPTOMICINA TIGECICLINA MINOCICLINA COTRIMOXAZOLO DALBAVANCINA ACIDO FUSIDICO CEFTAROLINA RIFAMPICINA TELAVANCINA ORITAVANCINA E. Coli ESBL + Concia E. Klebsiella Infections KPC-producing K. pneumoniae – the Italian epidemic late 2008 The first reported cases of KPC-Kp Giani et al – JCM 2009 Santoriello et al – unpublished early 2011 Fontana et al – BMC Res Notes 2010 Marchese et al – J Chemother 2010 Ambretti et al – New Microb 2010 Gaibani et al – Eurosurv 2011 Mezzatesta et al – CMI 2011 Agodi et al – JCM 2011 Richter et al – JCM 2011 Di Carlo et al – BMC Gastroenterol 2011 Rossolini GM – unpublished late 2012 AMCLI – CoSA CRE network Frasson et al – JCM 2012 ARISS – CoSA survey 2012 Core antibiotics and dosing regimens used for carbapenemcarbapenem-resistant Klebsiella pneumoniae infections. Drug PK:PD parameter Typical loading dose† Maintenance dose Meropenem 40% fTime > MIC 2000 mg 2000 mg every 8 h 4-h infusion CrCL 50 ml/min: standard dose CrCL 26–50: reduce dose by 50% CrCL 26 ml/min or HD/CVVHD: use renally-adjusted dose with intermittent infusion Colistin‡ fAUC:MIC 25–50 Loading dose CBA (mg) = colistin Cp § × 2 × weight (kg)¶ Daily dose of CBA (mg) colistin = Cp § (1.50 × CrCL × 30) Recommended dosage intervals based on CrCL#: 10 ml/min/1.73 m2: every 12 h, 10–70 ml/min/1.73 m2 every 8–12 h and 70 ml/min/1.73 m2: every 8–12 h Intermittent HD dosing: daily dose of CBA on a non-HD day to achieve each 1.0 mg/l colistin = Cp § = 30 mg Supplemental dose of CBA on a HD day††: add 50% to the daily maintenance dose if the supplemental dose is administered during the last hour of the HD session, or add 30% to the daily maintenance dose if the supplemental dose. Twice-daily dosing is suggested Continuous renal replacement: daily dose of CBA to achieve each 1.0 mg/l colistin Cp § target 192 mg. Doses may be given every 8–12 h Tigecycline fAUC:MIC 1 100–200 mg 50–100 mg every 12 h 'High-dose' therapy 200-mg loading dose, then 100 mg once daily Gentamicin fAUC:MIC 156 No loading dose recommendation 5 mg/kg/day for MIC <1; 7 mg/kg for MIC >2 Dose adjustment for renal dysfunction is guided by plasma concentration monitoring Fosfomycin 60% fTime > MIC Rifampin fAUC:MIC (not elucidated as monotherapy for Gram negatives) No loading dose recommendation No loading dose recommendation 8000 mg every 12 h 10 mg/kg every 12 h Petrosillo N: Expert Rev Anti Infect Ther. 2013;11:159 Which carbapenem ? Imipenem: better microbiological activity but suboptimal PK/PD profile Imipenem 1 g tid (in 3-4hrs) no PD target and risk of seizures HD Meropenem (2 g. tid), no neurotoxicity but inadequate serum levels for strains with MIC > 32 mg/l Synergism “in vitro” observed between imipenem/meropenem and ertapenem ( “double shot” therapy) Acinetobacter is a gram-negative coccobacillus Gram’s Staining of Sputum Specimen from a Patient with Suspected Ventilator-Associated Pneumonia Munoz-Price LS: N Engl J Med 2008;358:1271 The capacity of this pathogen to persist on surfaces in hospital setting is due to its ability to form biofilm on inanimate surfaces. McQueary CN et al. J Microb 2011; 49:243-50 Which is the treatment for MDR A baumannii? Terapia Acinetobacter MDR Ampicillina/sulbactam 3gx4/die Colimicina carico 9 milioni poi 4,5 milioni x2 + Rifampicina 600/900 mg /die +/- Carbapenemico Colimicina + Tigeciclina (sino a 100/150 mg x 2 die) Colimicina + Ampicillina /sulbactam Psudomonas Aeruginosa Pseudomonas aeruginosa Paradigma dell’antibiotico resistenza Tutti i meccanismi di resistenza conosciuti sono presenti in questa specie Fronteggia attacchi multidirezionali Sistemi di efflusso Verona 19-01-2013 E.Concia Pseudomonas aeruginosa infections - Mono vs combination therapy- Bassetti M et al. Curr Med Chem 2008; 15:517-22 Pseudomonas Aer. :Terapia Ceppi non MDR: Beta lattamico (Pip-Tazo , CP, Ceph antipseudomonas) + Aminoglicoside o Ciprofloxacina Ceppi resistenti ai carbapenemici: Colistina + Rifampicina (+/- carbapenemico infusione prolungata) Ceftazidime/Cefepime/Pip-Taz/Imipenem/Meropenem + Cipro/Levofloxacina/Amikacina Enterococchi (foecalis/ foecium) In conclusione… Germi multi-resistenti Farmaci Selezione Mani Trasmissione 1 Non trattare MAI i pazienti colonizzati 2 Non usare la Colimicina o la Fosfomicina da sola 3 Nelle infezioni da MDR scegliere antibiotico e dose sul valore di CMI in rapporto a breakpoint 4 In caso di pan resistenze chiedere al laboratorio studi di sinergia in vitro 5 I tentativi di decolonizzare ( es Gentamicina p.os ) non hanno sufficiente documentazione Quale strategia allora perseguire? Piani per il controllo delle infezioni: -epidemiologia -formazione -allarmi eventi sentinella Uso prudente e ragionato degli antibiotici Epidemiologia molecolare locale in rete con il resto del territorio [email protected]