1、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 prob
2、lem 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 Revie
3、w the mechanisms of resistance Identify ways to combat antimicrobial resistance Review principles of pharmacokinetics and pharmacodynamics Introduce antimicrobial stewardship,Mechanisms of Resistance,Enzymatic inhibitionDecreased uptakeIncreased exportAltered targetMetabolic bypass,Transfer of Resis
4、tance,Troublesome Bacteria Ability to “escape” the effects of current antimicrobial therapy,Enterococcus faeciumStaphylococcus aureusKlebsiella pneumoniaeAcinetobacter baumanniiPseudomonas aeruginosaEnterobacter species,ESKAPE,Redefining ESKAPE as ESCAPE,Enterococcus faeciumStaphylococcus aureusClos
5、tridium difficileAcinetobacter baumanniiPseudomonas aeruginosaEnterobacteriaceae,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 recentl
6、y 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
7、,Resistance in Gram Positive Bacteria,MRSA NNIS (2004) 60% of S. aureus are methicillin resistant Nosocomial mecA gene encodes low affinity for PBP resulting in resistance to all beta-lactams Usually multi-drug resistant Community-acquired More virulent Panton-Valentine leukocidin Skin and soft tiss
8、ue infections in children and young adults Usually susceptible to non beta-lactam drugsVISA Cell wall thickeningVRSA Horizontal transfer of a vanA gene from VRE,Resistance in Gram Negative Bacteria: Non-fermenters,Acinetobacter Uncommon in most U.S. medical centers Incidence as high as 10% in some g
9、eographic 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
10、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
11、 pneumoniae carbapenemase Metallo-beta-lactamases ampC beta-lactamase + loss of outer membrane channels,Characteristics of Beta-Lactamases,Resistance Among Intensive Care Unit Patients: 1995 - 2004,Source: National Nosocomial Infections Surveillance (NNIS) System,SERH Antibiogram 2009 Summary,Clostr
12、idium difficile infection rates at St. Elizabeth Regional Health,Significance of Antibiotic Resistance in the Intensive Care Unit,p0.001,p0.001,Kollef et al. Chest 1999; 115: 462-74,N = 655 ICU patients with infection 169/655 (25.8%) received inadequate therapy,Significance of Antibiotic Resistance
13、in Surgical Site Infections,479 patients: 165 MSSA, 121 MRSA,193 controls,Engemann JJ, et al. CID 2003; 36:592-8,Hospital and Societal Costs of Antimicrobial-Resistant Infections (ARIs),An economic analysis of the Chicago Antimicrobial Resistant Project dataset,188/1391 patients (13.5%) with ARI,Rob
14、erts RP et al. Clin Infect Dis 2009;49: 1175-84, As Antibiotic Options Decline Rapidly,12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults,Prevent Infection 1. Vaccinate 2. Get the catheters outDiagnose & Treat Effectively 3. Target the pathogen 4. Access the experts,Use Antimicrobials
15、 Wisely 5. Practice antimicrobial control 6. Use local data 7. Treat infection, not contamination 8. Treat infection, not colonization 9. Know when to say “no” to vanco 10. Stop treatment when cured or infection unlikelyPrevent Transmission 11. Isolate the pathogen 12. Break the chain of contagion,S
16、ource: Centers for Disease Control,Antimicrobial Stewardship,A rational, systematic approach to the use of antimicrobial agents in order to achieve optimal patient outcomesCorrect Drug Cure/prevent Infection Right Dose Minimize Toxicity Appropriate Duration Decrease Resistance,IDSA Guidelines: Antim
17、icrobial Stewardship,Core Strategies Prospective audit with intervention and feedbackFormulary restriction and pre-authorization,Supplements Education Guidelines/clinical pathways IV to PO Dose optimization De-escalation Antimicrobial order forms,Pharmacokinetic/Pharmacodynamic Relationships,Time ab
18、ove MIC,Area Under the Curve (AUC/MIC),Peak (Peak/MIC),MIC,Time,Drug Concentration,PAE,Increasing Efficacy of Antibiotics,Antimicrobial Stewardship at St. Elizabeth Regional Health,Automatic IV to PO for select antimicrobialsAutomatic 10-day stop for select antimicrobialsDosage Optimization Vancomyc
19、in Aminoglycosides Renal dosing PK/PD dosing,Getting to the Goal,Getting to the Goal,Primary GoalOptimize clinical outcomes while minimizing the unintended consequences of antimicrobial useSuch as: toxicity, selection of pathogenic organisms and emergence of bacterial resistance,JCAHO Patient Safety
20、 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 leanSome newer agents for MRSA Few novels agents for other ESKAPE pathogens NO new agents for
21、 infections due to MDR gram negative infections None represent more than incremental advances over current therapies availableClinical Infectious Diseases 2009; 48: 1-12,Carbapenem Resistance,Emerging problem seen with Pseudomonas, Acinetobacter and EnterbacteriaceaeRisk factors include ICU stay, pr
22、olonged healthcare exposure, indwelling devices, and antibiotic exposureSeverely limits treatment optionsOutbreaks reported in both single and multiple institutions,Klebsiella pneumonia:Carbapenemases (KPCs),Plasmid-mediated carbapenemaseKPC- producing strains of Klebsiella pneumonia and other Enter
23、obacteriaceaeKPC-3: Outbreak in Brooklyn, NY 24% of K. pneumonia infections were due to KPCsCountry 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 me
24、ropenem 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 organismNow being seen in general hospital population
25、and nursing homesAntimicrobial resistance is a MAJOR concern,Detroit Medical Center data 2003 to 2008,Number isolates up from 566 to 1239Susceptibilities cut greater than 50% for : Imipenem, amp/sub, Ceftaz, Cipro, Tmp/Smx, AmikOnly one not cut by half was Tobramycin,Reddy, ACC in print,Clinical App
26、lication 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 trea
27、tment 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 w
28、hich 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 10% for MIC values = 8 mcg/ml3.375g
29、m IV q8h ( 4 hr infusion)92% for MIC values = 16 mcg/ml 100% for MIC values = 8mcg/mlLodise TP, et al. Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on B-lactam antibiotics: insights from the society of Infectious Diseases Pharmacists. Pharmacotherapy2006. 26:13
30、20-32.,Improved outcomes noted with EI Piperacillin/ Tazobactam,In patients with high risk of mortality APACHE score 17Extended infusion Pip/tazo compared to standard intermittent infusionssignificantly lowered the 14 day mortality rates Significantly lowered median hospital LOSLodise TP, et al. Pip
31、eracillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007; 44:357-63.,Dosing Conversion,Improved f T MIC shown with EI Meropenem,In patients with Ventilator associated pneumonia Meropenem 1gm IV q8h (bolus dosing) f
32、 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/mlJaruratanasirikul, S., et al. Comparison of the pharmacodynamics of meropenem in parients with ventilator associated pneumo
33、nia 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 sepsisObjective to compare plasma and SQ concentrations of meropenem Intermittent bolus dosing Extended infusion Conti
34、nuous 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.,Meropene
35、m 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 tab
36、le,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 administr
37、ation? Monte Carlo dosing similairities and subcutaneous tissue distribution. Journal of Antimicrobial Chemotherapy 2009.,Meropenem in critically ill patients,Dose Conversion,Other items for implementation,Compatability charts have been developed for nursing, pharmacists and physicians to be posted
38、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 librariesCan show cost savings in addition to improving care by using less grams per day of antibiotic,Questions?,
