Pesky Gram Negatives: Just When You Thought It Couldn t Get Worse

1. Pesky Gram Negatives: Just When You Thought It Couldn�t Get Worse Ruth Carrico PhD RN CIC Assistant Professor School of Public Health and Information Sciences University of Louisville ruth.carrico@louisville.edu

2. Objectives Review emerging multidrug resistant gram negative organisms Describe their relevance to infection prevention and control Identify current challenges in infection prevention response

3. The Impact of Antimicrobial-Resistant Gram-Negative Infections Resistance to antimicrobial agents is increasing among many gram-negative pathogens Infection with resistant pathogens is associated with negative health outcomes Mortality/morbidity Length of ICU and hospital stay Healthcare costs Few antibiotic choices remain Highlights the need to optimize existing classes of antimicrobials through stewardship and infection prevention

4. Resistance Impact Over past decade, CDC has documented downward trend in infection rates in four major anatomic sites: Bloodstream Respiratory tract Urinary tract Wounds At same time, infection rates due to resistant pathogens are increasing

5. Multi-Drug Resistant Gram Negative Rods (GNR): CDC Definition MDR: Resistant to =3 classes* XDR: Susceptible to =2 agents Pan resistance: Resistant to all available antimicrobials Current MDRO gram negatives include E. coli, P. aeruginosa, K. pneumoniae, K. oxytoca, A. baumanii * Classes: Beta-lactams, fluoroquinolones, aminoglycosides, carbapenems

6. Review of Selected Antimicrobials Beta-lactams Penicillins and cephalosporins Fluoroquinolones Ciprofloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin Aminoglycosides Amikacin, Gentamicin, Streptomycin, Tobramycin, Kanamycin, Neomycin Carbapenems Doripenem, Meropenem, Ertapenem, Imipenem

7. Emergence of MDR Organisms

8. Normal Antimicrobial function Enzyme from your own body activates the antibiotic (metabolizes it) and it becomes active or available for use. The active antibiotic is able to bind to the receptor (wherever it is--) and start to workEnzyme from your own body activates the antibiotic (metabolizes it) and it becomes active or available for use. The active antibiotic is able to bind to the receptor (wherever it is--) and start to work

9. Normal Antimicrobial Function When it works, all of the antibiotics are able to bind to their appropriate receptors and the result it cell death (lysis). Everything worked like it is supposed to. There are ample opportunities for the process to fail at specific steps in the process. When it works, all of the antibiotics are able to bind to their appropriate receptors and the result it cell death (lysis). Everything worked like it is supposed to. There are ample opportunities for the process to fail at specific steps in the process.

10. Inability to Get to the Targeted Site

11. Change in the Receptor Bacterial cell receptor changes so the antibiotic cannot attach and get into the cell. The target site changes shape. Square peg into round hole.Bacterial cell receptor changes so the antibiotic cannot attach and get into the cell. The target site changes shape. Square peg into round hole.

12. Inactivation by an Enzyme Enzyme made by bacterium changes the active antibiotic into a different inactive formEnzyme made by bacterium changes the active antibiotic into a different inactive form

13. Inactivation by an Enzyme Enzyme made by bacterium changes the active antibiotic into a different inactive formEnzyme made by bacterium changes the active antibiotic into a different inactive form

14. Gram-Negative Pathogens:the Reality Pathogens encountered in healthcare institutions in North America, Europe, and Asia are, for the most part, similar Truly a worldwide problem Risk factors universal: Device use Antimicrobial overprescribing

15. Antimicrobial Resistance in Gram-Negative Infections Resistance is a complex problem Multiple/concurrent mechanisms Expanding mechanisms >500 discrete b-lactamases Evolution of carbapenemases Efflux pumps Permeability changes Selective antimicrobial pressure favors amplification of resistant bacteria

16. Extended Spectrum Beta-Lactamase (ESBL) Producers Enterobacterial resistance to 3rd generation cephalosporins caused by production of ESBL Beta-lactamase enzymes destroy the beta-lactam ring so that the antibiotic cannot bind to the PBP and interfere with cell wall synthesis Renders several classes of antimicrobials ineffective against the producing organism(s) Leads to difficulty in treatment, use of broader spectrum agents, increases collateral damage Carbapenems used for treatment

17. Enterobacteriaceae Citrobacter Enterobacter Escherichia coli Klebsiella Morganella morganii Proteus Providencia Salmonella Serratia Shigella Yersenia

18. Why Don�t We Treat ESBLs Like Other MDROs? Colonized state less profound and problematic than gram positives (MRSA, VRE)- we think! Less readily recognized in the laboratory setting Our practice evidence is very thin If isolation is not used, standard precautions and hand hygiene must be a main prevention activity

19. Extended Spectrum ?-lactamases (ESBLs) Risk Factors for Colonization/Infection* Hospitalization Nursing home residency Length of hospital/ICU stay Severity of illness Antibiotic exposure (esp. ceftazidime, aztreonam) Invasive devices/instrumentation

20. Carbapenem Resistance Widespread use of carbapenems for suspected ESBL infection has contributed to resistance due to selection Emergence of carbapenemase (a group of beta-lactamases) in enterobacteriaceae Klebsiella pneumoniae carbapenemase (KPC)-producing organisms Klebsiella spp. Enterobacter spp. E. coli Serratia spp.

21. Klebsiella pneumoniae carbapenemase (KPC)-producing organisms Resistant to carbapenems: MICs >32 mg/L Generally susceptible to tigecycline Further studies are needed to ascertain risk factors (East coast) Available data describe patients with infections caused by KPC-producing organisms as: Receiving long courses of broad spectrum antibiotics Prolonged ICU stays

22. Current Status of Antimicrobials No new classes 1968-2000 Since 2000, only 4 new classes approved by FDA Linezolid Streptogramins Daptomycin Tigecycline Apart from Tigecycline, no new class of agents against Gram-negative organisms

23. Principles of Antimicrobial Use

24. Principles of Antimicrobial Use

25. Mechanisms of Action

27. Antimicrobial Therapy

28. Aminoglycosides

29. Transmission of Resistant Organisms Contact with healthcare worker Lack of hand hygiene, inadequate patient care techniques, contaminated supplies/equipment Failure to implement contact precautions (at all or early enough) Inadequate environmental attention Promoting of resistance through inappropriate antimicrobial therapy Failure to identify prevention breaches and intervene

32. MDR Infection: General Principles

34. Strategies to Prevent Selection

36. Strategies to Prevent Selection

38. Elements of a Prevention Program

39. Competent Workforce Understands how transmission occurs Able to apply this knowledge in preventing transmission Recognizes who is involved in preventing transmission Able to apply the knowledge regarding transmission prevention in all settings Applies critical thinking skills to problem solve Actively collaborates with others in working toward the goal of transmission prevention

40. Applying Competencies KPCs/ESBLs/C. difficile/MRSA Role of microbes in disease Transmission Precautions Occupational/Employee health-protecting patient Occupational/Employee health-protecting HCW Problem solving Preparedness

41. The Healthcare Worker of Tomorrow

42. Shared Learning Website www.infectionpreventiontools.com