多重耐药细菌的抗生素选择(英文)Extending-Our-Options-for-Multi-dr.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Extending Our Options for Multi-drug Resistant Pathogens,Carol Miller,PharmD,BCPS,Katherine Pickerill,PharmD,February 9,2011,Why is Resistance a Concern?,Resistant organisms are becoming commonplace,Bacterial resistance often results in treatment failure and increased mortality and cost,The problem is no longer confined to the hospital setting,Bacterial resistance will continue to worsen if not addressed,There are no antibiotics on the immediate horizon with activity against these multi-drug resistant pathogens,Objectives,Describe the magnitude of the problem of antibiotic resistance,Review the mechanisms of resistance,Identify ways to combat antimicrobial resistance,Review principles of pharmacokinetics and pharmacodynamics,Introduce antimicrobial stewardship,Mechanisms of Resistance,Enzymatic inhibition,Decreased uptake,Increased export,Altered target,Metabolic bypass,Troublesome Bacteria,Ability to“escape”the effects of current antimicrobial therapy,Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa,Enterobacter species,ESKAPE,Redefining ESKAPE as ESCAPE,Enterococcus faecium,Staphylococcus aureus,Clostridium difficile,Acinetobacter baumannii,Pseudomonas aeruginosa,Enterobacteriaceae,ESCAPE,Acknowledges the growing virulence of,C.difficile,Captures,Klebsiella,Enterobacter,and other resistant species including,E.coli,and,Proteus sp,.,Resistance in Gram Positive Bacteria,VRE,Non-existent as recently as 1989,NNIS report(2004)30%of all enterococcal isolates are resistant,Mediated by vanA and vanB genes resulting in alteration of target site,Clonal spread via poor infection control,Various antibiotics may lead to VRE colonization,Anti-enterococcal activity,Biliary excretion,Anaerobic activity,Resistance in Gram Negative Bacteria:Non-fermenters,Acinetobacter,Uncommon in most U.S.medical centers,Incidence as high as 10%in some geographic locations,Carbapenems are drug of choice,Pseudomonas aeruginosa,Multi-drug resistance increasing nationwide,Fluoroquinolones:29%resistance(NNIS 2004),Beta-lactams:metallo-beta-lactamase producing strains have been reported,Resistance in Gram Negative Bacteria:Enterobacteriaceae,ESBLs a growing concern,Resistant to all penicillins,cephalosporins,and aztreonam,Carbapenems are the drug of choice,Fluoroquinolone resistance,NNIS 2004 report:8%,E.coli,resistant,Chromosomal and plasmid mediated alterations in target site or decreased access to target,Carbapenem resistance,Klebsiella pneumoniae,carbapenemase,Metallo-beta-lactamases,ampC beta-lactamase+loss of outer membrane channels,Resistance Among Intensive Care Unit Patients:1995-2004,Source:National Nosocomial Infections Surveillance(NNIS)System,Clostridium difficile,infection rates at St.Elizabeth Regional Health,Significance of Antibiotic Resistance in the Intensive Care Unit,p0.001,pMIC,Daptomycin,Concentration dependent,AUC:MIC,Cmax:MIC,Linezolid,Time dependent,TMIC,Macrolides,Time dependent,TMIC,Metronidazole,Concentration dependent,AUC:MIC,Quinolones,Concentration dependent,AUC:MIC,Tetracyclines,Time dependent,AUC:MIC,Vancomycin,Time dependent,AUC:MIC,Antimicrobial Stewardship at St.Elizabeth Regional Health,Automatic IV to PO for select antimicrobials,Automatic 10-day stop for select antimicrobials,Dosage Optimization,Vancomycin,Aminoglycosides,Renal dosing,PK/PD dosing,Getting to the Goal,JCAHO Patient Safety Goal#7,Preventing Multidrug Resistant Organism infections,Such as,Reduce risk of healthcare associated infections,C.dif.,MRSA,KPC,NO Drugs,Late stage clinical development pipeline remains unacceptably lean,Some newer agents for MRSA,Few novels agents for other ESKAPE pathogens,NO,new agents for infections due to MDR gram negative infections,None represent more than incremental advances over current therapies available,Clinical Infectious Diseases 2009;48:1-12,Carbapenem Resistance,Emerging problem seen with Pseudomonas,Acinetobacter and Enterbacteriaceae,Risk factors include ICU stay,prolonged healthcare exposure,indwelling devices,and antibiotic exposure,Severely limits treatment options,Outbreaks reported in both single and multiple institutions,Klebsiella pneumonia:,Carbapenemases(KPCs),Plasmid-mediated carbapenemase,KPC-producing strains of,Klebsiella pneumonia,and other,Enterobacteriaceae,KPC-3:Outbreak in Brooklyn,NY,24%of,K.pneumonia,infections were due to KPCs,Country wide outbreak in Israel,Bratu,AAC,2005;Quale,CID,2004;Leavitt,ACC,2007,KPCs,Spreading in Mid-Atlantic in US and through US even Midwest(Michigan/DMC),May appear susceptible to imipenem or meropenem but with borderline MICs,Usually ertapenem resistant,Usually only susceptible to colistin,tigecyline,and select aminoglycosides,Easily spread in hospitals,Single traveler can introduce,Acinetobacter baumannii,Traditionally only an ICU organism,Now being seen in general hospital population and nursing homes,Antimicrobial resistance is a MAJOR concern,Detroit Medical Center data 2003 to 2008,Number isolates up from 566 to 1239,Susceptibilities cut greater than 50%for:,Imipenem,amp/sub,Ceftaz,Cipro,Tmp/Smx,Amik,Only one not cut by half was Tobramycin,Reddy,ACC in print,Clinical Application of Pharmacokinetic and Pharmacodynamic Principles,Using high dose,aggressive therapy in patients with serious systemic infections,Especially for empiric therapy for patients at high risk for MDR pathogens,Consider PK/PD variability in patients ie.ICU patients,Consider consequences of treatment failures,Risk vs.benefit considerations,Increased efficacy,Increased toxicity,Antibiotic Extended Infusions(EI),Rationale supported for time-dependent killing antibiotics,Penicillins,cephalosporins,carbepenems,aztreonam,Antimicrobial PD describes the relationship between the time the in which free drug concentration exceeds the MIC of the organism(,f T MIC),GOAL:For B-Lactams serum level to remain above the MIC for 50%of the dosing interval,Probability of target attainment,Dosing 3.375gm IV q6h(30 min infusion),90%Only for MIC values 1mcg/ml,20ml/min or CRRT,Piperacillin/Tazobactam 4.5gm IV q8hr,(30 min),Piperacillin/Tazobactam 3.375gm IV q 8hr,(4 hr infusion,),Piperacillin/Tazobactam 3.375gm IV q6hr,(30 min),Piperacillin/Tazobactam 3.375gm IV q 8h,(30 min),Piperacillin/Tazobactam 2.25gm IV q6hr,(30 min),Patients with creatinine clearance=MIC shown with EI Meropenem,In patients with Ventilator associated pneumonia,Meropenem 1gm IV q8h(bolus dosing),f,T MIC 50%only for MIC for 4 mcg/ml,Meropenem 1gm IV q8h(over 3 hours),f,T MIC 50%for MIC of 8 mcg/ml,Meropenem 2 gm IV q8h(over 3 hours),f,T MIC 50%for MIC of 16 mcg/ml,Jaruratanasirikul,S.,et al.Comparison of the pharmacodynamics of meropenem in parients with ventilator associated pneumonia following administration by the 3 hour infusion or bolus injection.AAC April 2005;1337-39.,Improved,f,T MIC shown with EI Meropenem shown again,In critically ill patients with sepsis,Objective to compare plasma and SQ concentrations of meropenem,Intermittent bolus dosing,Extended infusion,Continuous infusion,Roberts J.A.,et.al.Meropenem dosing in Critically ill patients with sepsis and without renal dysfunction:intermittent bolus versus continuous administration?Monte Carlo dosing similairities and subcutaneous tissue distribution.Journal of Antimicrobial Chemotherapy 2009.,Meropenem in declining renal function,Objective to evaluate steady-state kinetics and,pharmacodynamics,of,meropenem,500mg every 6,8,and 12 hours,based upon patient renal function.,Patients were grouped based upon their renal,functionas,to which dose and interval they received based upon the following table,Creatinine Clearance,(ml/min),Dose,Greater than 60,500mg q6h,30 60,500mg q8h,10-29,500mg q12h,Less than 10,500mg q24h,Cheatham,S.C.Steady-State Pharmacokinetics and Pharmacodynamics of Meropenem in Hospitalized Patients.Pharmacotherapy 2008.28(6):691-698.,Roberts J.A.,et.al.Meropenem dosing in Critically ill patients with sepsis and without renal dysfunction:intermittent bolus versus continuous administration?Monte Carlo dosing similairities and subcutaneous tissue distribution.Journal of Antimicrobial Chemotherapy 2009.,Meropenem in critically ill patients,Dose Conversion,WHEN ORDER IS RECEIVED FOR,INTERCHANGE WITH,Meropenem 1gm IV q8hr(30 min)Meropenem 500 mg(over 3 hours)iv every 6hrs,This is the normal dose;and for CRRT patients,For patients with renal impairment:,Creatinine Clearance 10-49 ml/min,Meropenem 500mg IV q 8hr (3 hr infusion),Patients with creatinine clearance,=10ml/min,on hemodialysis or peritoneal dialysis,Meropenem 500mg IV q12(3 hour infusion),NOTE:FOR MENINGITIS:DOSE AT 2GM IV q8h(over 3 hours)adjust for renal impairment,Other items for implementation,Compatability charts have been developed for nursing,pharmacists and physicians to be posted on GATOR and in medication rooms,Working with Nursing for education purposes,Planning to update SMART pump libraries,Can show cost savings in addition to improving care by using less grams per day of antibiotic,Other items for implementation,Planning to update SMART pump libraries,Can show cost savings in addition to improving care by using less grams per day of antibiotic,Questions?,