多重耐药细菌的抗生素选择（英文ppt）extendingour options for multidrug resistant

Extending Our Options for Extending Our Options for Multi-drug Resistant PathogensMulti-drug Resistant Pathogens Carol Miller, Carol Miller, PharmDPharmD, BCPS, BCPS Katherine Katherine PickerillPickerill, , PharmDPharmD February 9, 2011February 9, 2011 Why is Resistance a Concern?Why is Resistance a Concern? Resistant organisms are becoming Resistant organisms are becoming commonplacecommonplace Bacterial resistance often results in treatment Bacterial resistance often results in treatment failure and increased mortality and costfailure and increased mortality and cost The problem is no longer confined to the The problem is no longer confined to the hospital settinghospital setting Bacterial resistance will continue to worsen if not Bacterial resistance will continue to worsen if not addressedaddressed There are no antibiotics on the immediate There are no antibiotics on the immediate horizon with activity against these multi-drug horizon with activity against these multi-drug resistant pathogensresistant pathogens ObjectivesObjectives Describe the magnitude of the problem of Describe the magnitude of the problem of antibiotic resistanceantibiotic resistance Review the mechanisms of resistanceReview the mechanisms of resistance Identify ways to combat antimicrobial Identify ways to combat antimicrobial resistanceresistance Review principles of pharmacokinetics and Review principles of pharmacokinetics and pharmacodynamicspharmacodynamics Introduce antimicrobial stewardshipIntroduce antimicrobial stewardship Mechanisms of ResistanceMechanisms of Resistance Enzymatic inhibitionEnzymatic inhibition Decreased uptakeDecreased uptake Increased exportIncreased export Altered targetAltered target Metabolic bypassMetabolic bypass Transfer of ResistanceTransfer of Resistance Troublesome BacteriaTroublesome Bacteria Ability to “escape” the effects of current antimicrobial therapyAbility to “escape” the effects of current antimicrobial therapy EnterococcusEnterococcus faeciumfaecium Staphylococcus Staphylococcus aureusaureus KlebsiellaKlebsiella pneumoniaepneumoniae AcinetobacterAcinetobacter baumanniibaumannii Pseudomonas Pseudomonas aeruginosaaeruginosa EnterobacterEnterobacter species species Redefining ESKAPE as ESCAPERedefining ESKAPE as ESCAPE EnterococcusEnterococcus faeciumfaecium Staphylococcus Staphylococcus aureusaureus Clostridium Clostridium difficiledifficile AcinetobacterAcinetobacter baumanniibaumannii Pseudomonas Pseudomonas aeruginosaaeruginosa EnterobacteriaceaeEnterobacteriaceae Acknowledges the growing virulence of C. difficile Captures Klebsiella, Enterobacter, and other resistant species including E. coli and Proteus sp. Resistance in Gram Positive Resistance in Gram Positive BacteriaBacteria VREVRE Non-existent as recently as 1989Non-existent as recently as 1989 NNIS report (2004) 30% of all NNIS report (2004) 30% of all enterococcalenterococcal isolates isolates are resistantare resistant Mediated by Mediated by vanAvanA and and vanBvanB genes resulting in genes resulting in alteration of target sitealteration of target site ClonalClonal spread via poor infection control spread via poor infection control Various antibiotics may lead to VRE colonizationVarious antibiotics may lead to VRE colonization Anti-Anti-enterococcalenterococcal activity activity BiliaryBiliary excretion excretion Anaerobic activityAnaerobic activity Resistance in Gram Positive BacteriaResistance in Gram Positive Bacteria MRSAMRSA NNIS (2004) 60% of NNIS (2004) 60% of S. S. aureusaureus are are methicillinmethicillin resistant resistant NosocomialNosocomial mecAmecA gene encodes low affinity for PBP resulting in gene encodes low affinity for PBP resulting in resistance to all beta-resistance to all beta-lactamslactams Usually multi-drug resistantUsually multi-drug resistant Community-acquiredCommunity-acquired More virulent Panton-Valentine More virulent Panton-Valentine leukocidinleukocidin Skin and soft tissue infections in children and young adultsSkin and soft tissue infections in children and young adults Usually susceptible to non beta-Usually susceptible to non beta-lactamlactam drugs drugs VISAVISA Cell wall thickeningCell wall thickening VRSAVRSA Horizontal transfer of a Horizontal transfer of a vanAvanA gene from VRE gene from VRE Resistance in Gram Negative Bacteria: Resistance in Gram Negative Bacteria: Non-Non-fermentersfermenters AcinetobacterAcinetobacter Uncommon in most U.S. medical centersUncommon in most U.S. medical centers Incidence as high as 10% in some geographic Incidence as high as 10% in some geographic locationslocations CarbapenemsCarbapenems are drug of choice are drug of choice Pseudomonas Pseudomonas aeruginosaaeruginosa Multi-drug resistance increasing nationwideMulti-drug resistance increasing nationwide FluoroquinolonesFluoroquinolones: 29% resistance (NNIS 2004): 29% resistance (NNIS 2004) Beta-Beta-lactamslactams: : metallo-beta-lactamasemetallo-beta-lactamase producing producing strains have been reportedstrains have been reported Resistance in Gram Negative Bacteria: Resistance in Gram Negative Bacteria: EnterobacteriaceaeEnterobacteriaceae ESBLsESBLs a growing concern a growing concern Resistant to all Resistant to all penicillinspenicillins, , cephalosporinscephalosporins, and , and aztreonamaztreonam CarbapenemsCarbapenems are the drug of choice are the drug of choice FluoroquinoloneFluoroquinolone resistance resistance NNIS 2004 report: 8% NNIS 2004 report: 8% E.coliE.coli resistant resistant Chromosomal and plasmid mediated alterations in Chromosomal and plasmid mediated alterations in target site or decreased access to targettarget site or decreased access to target CarbapenemCarbapenem resistance resistance KlebsiellaKlebsiella pneumoniaepneumoniae carbapenemasecarbapenemase Metallo-beta-lactamasesMetallo-beta-lactamases ampCampC beta- beta-lactamaselactamase + loss of outer membrane + loss of outer membrane channelschannels Characteristics of Beta-Characteristics of Beta-LactamasesLactamases Beta-Beta-lactamaselactamaseSpectrum of ResistanceSpectrum of Resistance Broad spectrumBroad spectrumPenicillinsPenicillins Narrow spectrum Narrow spectrum cephalosporinscephalosporins Extended spectrumExtended spectrumPenicillinsPenicillins MonobactamsMonobactams CephalosporinsCephalosporins (except (except cephamycinscephamycins) ) AmpCAmpCPenicillinsPenicillins MonobactamsMonobactams CephalosporinsCephalosporins (including (including cephamycinscephamycins) ) CarbapenemaseCarbapenemase - - MetalloMetallo-beta-enzymes-beta-enzymes - - KlebsiellaKlebsiella pneumoniaepneumoniae carbapenemasecarbapenemase (KPC) (KPC) PenicillinsPenicillins MonobactamsMonobactams CephalosporinsCephalosporins (including (including cephamycinscephamycins) ) CarbapenemsCarbapenems Resistance Among Intensive Care Resistance Among Intensive Care Unit Patients: 1995 - 2004Unit Patients: 1995 - 2004 Source: National Nosocomial Infections Surveillance (NNIS) System SERH SERH AntibiogramAntibiogram 2009 Summary2009 Summary Clostridium Clostridium difficiledifficile infection rates infection rates at St. Elizabeth Regional Healthat St. Elizabeth Regional Health Significance of Antibiotic Resistance in Significance of Antibiotic Resistance in the Intensive Care Unitthe Intensive Care Unit pMICTMIC DaptomycinDaptomycinConcentration dependentConcentration dependentAUC:MIC, AUC:MIC, Cmax:MICCmax:MIC LinezolidLinezolidTime dependentTime dependentTMICTMIC MacrolidesMacrolidesTime dependentTime dependentTMICTMIC MetronidazoleMetronidazoleConcentration dependentConcentration dependentAUC:MICAUC:MIC QuinolonesQuinolonesConcentration dependentConcentration dependentAUC:MICAUC:MIC TetracyclinesTetracyclinesTime dependentTime dependentAUC:MICAUC:MIC VancomycinVancomycinTime dependentTime dependentAUC:MICAUC:MIC Antimicrobial Stewardship at St. Antimicrobial Stewardship at St. Elizabeth Regional HealthElizabeth Regional Health Automatic IV to PO for select antimicrobialsAutomatic IV to PO for select antimicrobials Automatic 10-day stop for select antimicrobialsAutomatic 10-day stop for select antimicrobials Dosage OptimizationDosage Optimization VancomycinVancomycin AminoglycosidesAminoglycosides Renal dosingRenal dosing PK/PD dosingPK/PD dosing Getting to the Goal Getting to the Goal Getting to the Goal Getting to the Goal Primary GoalPrimary Goal Optimize clinical outcomes while Optimize clinical outcomes while minimizing the unintended consequences minimizing the unintended consequences of antimicrobial useof antimicrobial use Such as: toxicity, selection of pathogenic Such as: toxicity, selection of pathogenic organisms and emergence of bacterial organisms and emergence of bacterial resistanceresistance JCAHO Patient Safety Goal #7JCAHO Patient Safety Goal #7 Preventing Multidrug Resistant Organism Preventing Multidrug Resistant Organism infectionsinfections Such as Such as Reduce risk of healthcare associated Reduce risk of healthcare associated infections infections C. dif., MRSA, KPC C. dif., MRSA, KPC NO DrugsNO Drugs Late stage clinical development pipeline remains Late stage clinical development pipeline remains unacceptably leanunacceptably lean Some newer agents for MRSASome newer agents for MRSA Few novels agents for other ESKAPE pathogensFew novels agents for other ESKAPE pathogens NO NO new agents for infections due to MDR gram new agents for infections due to MDR gram negative infectionsnegative infections None represent more than incremental advances None represent more than incremental advances over current therapies availableover current therapies available Clinical Infectious Diseases 2009; 48: 1-12Clinical Infectious Diseases 2009; 48: 1-12 CarbapenemCarbapenem Resistance Resistance Emerging problem seen with Pseudomonas, Emerging problem seen with Pseudomonas, AcinetobacterAcinetobacter and and EnterbacteriaceaeEnterbacteriaceae Risk factors include ICU stay, prolonged Risk factors include ICU stay, prolonged healthcare exposure, indwelling devices, and healthcare exposure, indwelling devices, and antibiotic exposureantibiotic exposure Severely limits treatment optionsSeverely limits treatment options Outbreaks reported in both single and Outbreaks reported in both single and multiple institutions multiple institutions KlebsiellaKlebsiella pneumonia:pneumonia:CarbapenemasesCarbapenemases ( (KPCsKPCs) ) Plasmid-mediated Plasmid-mediated carbapenemasecarbapenemase KPC- producing strains of KPC- producing strains of KlebsiellaKlebsiella pneumonia pneumonia and other and other EnterobacteriaceaeEnterobacteriaceae KPC-3: Outbreak in Brooklyn, NYKPC-3: Outbreak in Brooklyn, NY 24% of 24% of K. pneumonia K. pneumonia infections were due to infections were due to KPCsKPCs Country wide outbreak in Israel Country wide outbreak in Israel Bratu, AAC, 2005; Quale, CID, 2004; Leavitt, ACC, 2007 KPCsKPCs Spreading in Mid-Atlantic in US and through Spreading in Mid-Atlantic in US and through US even Midwest ( Michigan/DMC) US even Midwest ( Michigan/DMC) May appear susceptible to May appear susceptible to imipenemimipenem or or meropenemmeropenem but with borderline but with borderline MICsMICs Usually Usually ertapenemertapenem resistant resistant Usually only susceptible to Usually only susceptible to colistincolistin , , tigecylinetigecyline, and select , and select aminoglycosidesaminoglycosides Easily spread in hospitals Easily spread in hospitals Single traveler can introduceSingle traveler can introduce AcinetobacterAcinetobacter baumanniibaumannii Traditionally only an ICU organismTraditionally only an ICU organism Now being seen in general hospital Now being seen in general hospital population and nursing homespopulation and nursing homes Antimicrobial resistance is a MAJOR Antimicrobial resistance is a MAJOR concernconcern Detroit Medical Center data 2003 to 2008Detroit Medical Center data 2003 to 2008 Number isolates up from 566 to 1239Number isolates up from 566 to 1239 Susceptibilities cut greater than 50% for : Susceptibilities cut greater than 50% for : ImipenemImipenem, amp/sub, , amp/sub, CeftazCeftaz, , CiproCipro, , Tmp/SmxTmp/Smx, , AmikAmik Only one not cut by half was Only one not cut by half was TobramycinTobramycin Reddy, ACC in print Clinical Application of Pharmacokinetic and Clinical Application of Pharmacokinetic and PharmacodynamicPharmacodynamic Principles Principles Using high dose, aggressive therapy in Using high dose, aggressive therapy in patients with serious systemic infections patients with serious systemic infections Especially for empiric therapy for patients at high Especially for empiric therapy for patients at high risk for MDR pathogensrisk for MDR pathogens Consider PK/PD variability in patients Consider PK/PD variability in patients ieie. ICU . ICU patientspatients Consider consequences of treatment failuresConsider consequences of treatment failures Risk vs. benefit considerationsRisk vs. benefit considerations Increased efficacyIncreased efficacy Increased toxicityIncreased toxicity Antibiotic Extended Infusions (EI) Antibiotic Extended Infusions (EI) Rationale supported for time-dependent Rationale supported for time-dependent killing antibiotics killing antibiotics PenicillinsPenicillins, , cephalosporinscephalosporins, , carbepenemscarbepenems, , aztreonamaztreonam Antimicrobial PD describes the relationship Antimicrobial PD describes the relationship between the time the in which free drug between the time the in which free drug concentration exceeds the MIC of the concentration exceeds the MIC of the organism ( organism ( f T MIC) f T MIC) GOAL: For B- GOAL: For B- LactamsLactams serum level to serum level to remain above the MIC for 50% of the dosing remain above the MIC for 50% of the dosing intervalinterval Probability of target attainmentProbability of target attainment Dosing 3.375gm IV q6h (30 min infusion)Dosing 3.375gm IV q6h (30 min infusion) 90% Only for MIC values 1mcg/ml 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 T MIC shown with EI MeropenemMeropenem In patients with Ventilator associated In patients with Ventilator associated pneumonia pneumonia MeropenemMeropenem 1gm IV q8h (bolus dosing) 1gm IV q8h (bolus dosing) f f T MIC 50 % only for MIC for 4 mcg/ml T MIC 50 % only for MIC for 4 mcg/ml MeropenemMeropenem 1gm IV q8h (over 3 hours) 1gm IV q8h (over 3 hours) f f T MIC 50 % for MIC of 8 mcg/ml T MIC 50 % for MIC of 8 mcg/ml MeropenemMeropenem 2 gm IV q8h (over 3 hours) 2 gm IV q8h (over 3 hours) f f T MIC 50 % for MIC of 16 mcg/ml T MIC 50 % for MIC of 16 mcg/ml JaruratanasirikulJaruratanasirikul, S., et al. Comparison of the , S., et al. Comparison of the pharmacodynamicspharmacodynamics of of meropenemmeropenem in in parientsparients with with ventilator associated pneumonia following administration by the 3 hour infusion or bolus injection. ventilator associated pneumonia following administration by the 3 hour infusion or bolus injection. AAC April 2005; 1337-39. AAC April 2005; 1337-39. Improved Improved f f T MIC shown with EI T MIC shown with EI MeropenemMeropenem shown again shown again In critically ill patients with sepsisIn critically ill patients with sepsis Objective to compare plasma and SQ Objective to compare plasma and SQ concentrations of concentrations of meropenemmeropenem Intermittent bolus dosing Intermittent bolus dosing Extended infusion Extended infusion Continuous infusion Continuous infusion Roberts J.A., et. al. Roberts J.A., et. al. MeropenemMeropenem dosing in Critically ill patients with sepsis and without renal dysfunction: dosing in Critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing intermittent bolus versus continuous administration? Monte Carlo dosing similairitiessimilairities and subcutaneous and subcutaneous tissue distribution. Journal of Antimicrobial Chemotherapy 2009. tissue distribution. Journal of Antimicrobial Chemotherapy 2009. MeropenemMeropenem in declining renal in declining renal functionfunction 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. Roberts J.A., et. al. MeropenemMeropenem dosing in Critically ill patients with sepsis and without renal dosing in Critically ill patients with sepsis and without renal dysfunction: intermittent bo