多重耐药细菌的抗生素选择（英文）extending our options for multidrug resistant pathogens

1、Extending Our Options for Multi-drug Resistant PathogensCarol Miller, PharmD, BCPSKatherine Pickerill, PharmDFebruary 9, 2011Why is Resistance a Concern?Resistant organisms are becoming commonplaceBacterial resistance often results in treatment failure and increased mortality and costThe problem is

2、no longer confined to the hospital settingBacterial resistance will continue to worsen if not addressedThere are no antibiotics on the immediate horizon with activity against these multi-drug resistant pathogensObjectivesDescribe the magnitude of the problem of antibiotic resistanceReview the mechan

3、isms of resistanceIdentify ways to combat antimicrobial resistanceReview principles of pharmacokinetics and pharmacodynamicsIntroduce antimicrobial stewardshipMechanisms of ResistanceEnzymatic inhibitionDecreased uptakeIncreased exportAltered targetMetabolic bypassTransfer of ResistanceTroublesome B

4、acteriaAbility to “escape” the effects of current antimicrobial therapyEnterococcus faeciumStaphylococcus aureusKlebsiella pneumoniaeAcinetobacter baumanniiPseudomonas aeruginosaEnterobacter speciesESKAPERedefining ESKAPE as ESCAPEEnterococcus faeciumStaphylococcus aureusClostridium difficileAcineto

5、bacter baumanniiPseudomonas aeruginosaEnterobacteriaceaeESCAPEAcknowledges the growing virulence of C. difficileCaptures Klebsiella, Enterobacter, and other resistant species including E. coli and Proteus sp.Resistance in Gram Positive BacteriaVRENon-existent as recently as 1989NNIS report (2004) 30

6、% of all enterococcal isolates are resistantMediated by vanA and vanB genes resulting in alteration of target siteClonal spread via poor infection controlVarious antibiotics may lead to VRE colonizationAnti-enterococcal activityBiliary excretionAnaerobic activityResistance in Gram Positive BacteriaM

7、RSANNIS (2004) 60% of S. aureus are methicillin resistantNosocomialmecA gene encodes low affinity for PBP resulting in resistance to all beta-lactamsUsually multi-drug resistantCommunity-acquiredMore virulent Panton-Valentine leukocidinSkin and soft tissue infections in children and young adultsUsua

8、lly susceptible to non beta-lactam drugsVISACell wall thickeningVRSAHorizontal transfer of a vanA gene from VREResistance in Gram Negative Bacteria: Non-fermentersAcinetobacterUncommon in most U.S. medical centersIncidence as high as 10% in some geographic locationsCarbapenems are drug of choice Pse

9、udomonas aeruginosaMulti-drug resistance increasing nationwideFluoroquinolones: 29% resistance (NNIS 2004)Beta-lactams: metallo-beta-lactamase producing strains have been reportedResistance in Gram Negative Bacteria: EnterobacteriaceaeESBLs a growing concernResistant to all penicillins, cephalospori

10、ns, and aztreonamCarbapenems are the drug of choiceFluoroquinolone resistanceNNIS 2004 report: 8% resistantChromosomal and plasmid mediated alterations in target site or decreased access to targetCarbapenem resistanceKlebsiella pneumoniae carbapenemaseMetallo-beta-lactamasesampC beta-lactamase + los

11、s of outer membrane channelsCharacteristics of Beta-LactamasesBeta-lactamaseSpectrum of ResistanceBroad spectrumPenicillinsNarrow spectrum cephalosporinsExtended spectrumPenicillinsMonobactams Cephalosporins (except cephamycins)AmpCPenicillinsMonobactams Cephalosporins (including cephamycins)Carbape

12、nemase - Metallo-beta-enzymes - Klebsiella pneumoniae carbapenemase (KPC)PenicillinsMonobactams Cephalosporins (including cephamycins)CarbapenemsResistance Among Intensive Care Unit Patients: 1995 - 2004Source: National Nosocomial Infections Surveillance (NNIS) SystemSERH Antibiogram2009 SummaryClos

13、tridium difficile infection rates at St. Elizabeth Regional HealthSignificance of Antibiotic Resistance in the Intensive Care UnitKollef et al. Chest 1999; 115: 462-74N = 655 ICU patients with infection169/655 (25.8%) received inadequate therapySignificance of Antibiotic Resistance in Surgical Site

14、Infections479 patients: 165 MSSA, 121 MRSA,193 controlsEngemann JJ, et al. CID 2003; 36:592-8Hospital and Societal Costs of Antimicrobial-Resistant Infections (ARIs)Medical costs attributable to ARI$18, 588 - $29,069/patientExcess LOS6.4 12.7 daysAttributable mortality+ 6.5%Societal costs$10.7 - $15

15、 millionAn economic analysis of the Chicago Antimicrobial Resistant Project dataset188/1391 patients (13.5%) with ARIRoberts RP et al. Clin Infect Dis 2009;49: 1175-84 As Antibiotic Options Decline Rapidly12 Steps to Prevent Antimicrobial Resistance: Hospitalized AdultsPrevent Infection1. Vaccinate2

16、. Get the catheters outDiagnose & Treat Effectively3. Target the pathogen4. Access the expertsUse Antimicrobials Wisely5. Practice antimicrobial control6. Use local data7. Treat infection, not contamination8. Treat infection, not colonization9. Know when to say “no” to vanco10. Stop treatment when c

17、ured or infection unlikelyPrevent Transmission11. Isolate the pathogen12. Break the chain of contagionSource: Centers for Disease ControlAntimicrobial StewardshipA rational, systematic approach to the use of antimicrobial agents in order to achieve optimal patient outcomesCorrect DrugCure/prevent In

18、fectionRight DoseMinimize ToxicityAppropriate DurationDecrease ResistanceIDSA Guidelines: Antimicrobial StewardshipCore StrategiesProspective audit with intervention and feedbackFormulary restriction and pre-authorizationSupplementsEducationGuidelines/clinical pathwaysIV to PO Dose optimizationDe-es

19、calationAntimicrobial order formsPharmacokinetic/Pharmacodynamic RelationshipsTime above MICArea Under the Curve (AUC/MIC)Peak (Peak/MIC)MICTimeDrug ConcentrationPAEIncreasing Efficacy of AntibioticsDrugBactericidal PatternPK-PD MeasureAminoglycosidesConcentration dependentCmax:MICBeta-lactamsTime d

20、ependentTMICDaptomycinConcentration dependentAUC:MIC, Cmax:MICLinezolidTime dependentTMICMacrolidesTime dependentTMICMetronidazoleConcentration dependentAUC:MICQuinolonesConcentration dependentAUC:MICTetracyclinesTime dependentAUC:MICVancomycinTime dependentAUC:MICAntimicrobial Stewardship at St. El

21、izabeth Regional HealthAutomatic IV to PO for select antimicrobialsAutomatic 10-day stop for select antimicrobialsDosage OptimizationVancomycinAminoglycosidesRenal dosingPK/PD dosingGetting to the Goal Getting to the Goal Primary GoalOptimize clinical outcomes while minimizing the unintended consequ

22、ences of antimicrobial useSuch as: toxicity, selection of pathogenic organisms and emergence of bacterial resistanceJCAHO Patient Safety Goal #7 Preventing Multidrug Resistant Organism infections Such as Reduce risk of healthcare associated infections C. dif., MRSA, KPC NO DrugsLate stage clinical d

23、evelopment pipeline remains unacceptably leanSome newer agents for MRSAFew novels agents for other ESKAPE pathogensNO new agents for infections due to MDR gram negative infectionsNone represent more than incremental advances over current therapies availableClinical Infectious Diseases 2009; 48: 1-12

24、Carbapenem ResistanceEmerging problem seen with Pseudomonas, Acinetobacter and EnterbacteriaceaeRisk factors include ICU stay, prolonged healthcare exposure, indwelling devices, and antibiotic exposureSeverely limits treatment optionsOutbreaks reported in both single and multiple institutions Klebsi

25、ella pneumonia:Carbapenemases (KPCs)Plasmid-mediated carbapenemaseKPC- producing strains of Klebsiella pneumonia and other EnterobacteriaceaeKPC-3: Outbreak in Brooklyn, NY24% of K. pneumonia infections were due to KPCsCountry wide outbreak in Israel Bratu, AAC, 2005; Quale, CID, 2004; Leavitt, ACC,

26、 2007KPCs 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 resistantUsually only susceptible to colistin , tigecyline, and select aminoglycosides Easily spread in hospitals Single tr

27、aveler can introduceAcinetobacter baumanniiTraditionally only an ICU organismNow being seen in general hospital population and nursing homesAntimicrobial resistance is a MAJOR concernDetroit Medical Center data 2003 to 2008Number isolates up from 566 to 1239Susceptibilities cut greater than 50% for

28、: Imipenem, amp/sub, Ceftaz, Cipro, Tmp/Smx, AmikOnly one not cut by half was Tobramycin Reddy, ACC in printClinical Application of Pharmacokinetic and Pharmacodynamic PrinciplesUsing high dose, aggressive therapy in patients with serious systemic infections Especially for empiric therapy for patien

29、ts at high risk for MDR pathogensConsider PK/PD variability in patients ie. ICU patientsConsider consequences of treatment failuresRisk vs. benefit considerationsIncreased efficacyIncreased toxicityAntibiotic Extended Infusions (EI) Rationale supported for time-dependent killing antibiotics Penicill

30、ins, cephalosporins, carbepenems, aztreonamAntimicrobial 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 intervalProbability of target attainm

31、entDosing 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)Piperacill

32、in/Tazobactam 2.25gm IV q6hr (30 min)Patients with creatinine clearance = MIC shown with EI MeropenemIn patients with Ventilator associated pneumonia Meropenem 1gm IV q8h (bolus dosing)f T MIC 50 % only for MIC for 4 mcg/mlMeropenem 1gm IV q8h (over 3 hours)f T MIC 50 % for MIC of 8 mcg/mlMeropenem

33、2 gm IV q8h (over 3 hours)f T MIC 50 % for MIC of 16 mcg/mlJaruratanasirikul, 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 show

34、n with EI Meropenem shown againIn critically ill patients with sepsisObjective 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 dysfunct

35、ion: intermittent bolus versus continuous administration? Monte Carlo dosing similairities and subcutaneous tissue distribution. Journal of Antimicrobial Chemotherapy 2009. Meropenem in declining renal functionObjective to evaluate steady-state kinetics and pharmacodynamics of meropenem 500mg every

36、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 tableCreatinine Clearance (ml/min) Dose Greater than 60 500mg q6h 30 60 500mg q8h 10 - 29 500mg q12h Less than 10 500mg q24h . 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 rena