1. Multidrug-resistant Organisms in Health Care Settings Sherman J. Alter, M.D. Division of Infectious Disease The Children’s Medical Center of Dayton Department of Pediatrics Boonshoft School of Medicine Wright State University Dayton, OH

3. NDM- beta lactamase organisms White nose fungus Monkeypox E. coli O104:H4 SARS Measles H5N1

6. Impact of multidrug-resistant organisms (MDROs) on the health care system Infections caused by MDROs are associated with worsened clinical outcomes, including an increased risk of death. MDRO infections are also associated with significantly increased costs to hospitals, mostly attributable to increased length of stay. Media, legislative, and regulatory pressures are additional factors compelling hospitals to more effectively control MDROs.

7. Factors that might increase antimicrobial resistance in hospitals Greater severity of illness of hospitalized patients More severely immunocompromised patients Newer devices and procedures in use Increased introduction of resistant organisms from the community Ineffective infection control and isolation practices and compliance Increased use of antimicrobial prophylaxis Increased empiric polymicrobial antibiotic therapy High antibiotic usage per geographic area per unit time Clin Infect Dis 1997; 25:584-99

8. Risk factors for health care-associated infections and infection with drug- resistant bacteria Risk factors for health care-associated infections Hospitalization for >2 days in preceding 90 days Residence in nursing home or long-term care facility Home infusion therapy, including antibiotics Long-term dialysis within 30 days Home wound care Family member with multidrug-resistant pathogen Risk factors for infection with antibiotic-resistant bacteria Antimicrobial therapy in preceding 90 days Current hospitalization for >5 days High frequency of antibiotic resistance in community or specific hospital unit Immunosuppression Peleg et al. N Engl J Med 2010;362:1804-13

9. Rationale for MDRO control Clinical consequences of MDROs Worsened patient morbidity/mortality Economic consequences of MDROs ↑ costs of managing individual patients, opportunity costs, cost of control programs Legislative mandates ↑ number of states require specific surveillance strategies; many promote or mandate public reporting. Pay-for-performance measures Proposals to MRSA in CMS programs linked to ↓ hospital reimbursement Public image and reputation Patient advocacy groups and media focused on MDRO preparedness Medicolegal liability Lawsuits linking MRSA infection with hospital/provider neglect From What Every Health Care Executive Should Know: The Cost of Antibiotic Resistance. Joint Commission Resources, 2009.

10. Elements of an effective multidrug resistant organism control program 1.MDRO and infection control risk assessment 2.MDRO and infection control performance assessment 3.Antibiotic stewardship 4.Transmission control 5.Education From What Every Health Care Executive Should Know: The Cost of Antibiotic Resistance. Joint Commission Resources, 2009.

11. Preventing antimicrobial resistance in health care settings Prevent Infections 1. Vaccinate 2. Get the catheters out Diagnose and treat infections effectively 3. Target the pathogen 4. Access the experts Use antimicrobials 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 antimicrobial treatment Prevent transmission 11. Isolate the pathogen 12. Break the chain of contagion http://www.cdc.gov/drugresistance/healthcare/ha/12steps_HA.htm

12. Antimicrobial Resistance: Key Prevention Strategies Optimize Use Prevent Transmission Prevent Infection Effective Diagnosis & Treatment Pathogen Antimicrobial-Resistant Pathogen Antimicrobial Resistance Antimicrobial Use Infection Susceptible Pathogen

13. Mortality associated with carbapenem resistant (CR) vs susceptible (CS) Klebsiella pneumoniae (KP) p<0.001 Patel G et al. ICHE 2008;29:1099-1106 OR 3.71 (1.97- 7.01 ) OR 4.5 (2.16-9.35)

14. Fact: Pre-discharge influenza and pneumococcal vaccination of at-risk hospital patients AND influenza vaccination of healthcare personnel will prevent infections. Prevent Infection Step 1: Vaccinate

15. Respiratory antibiotic prescription rates over the study period, demonstrating year ‐ to ‐ year variability, temporal correlation with Ontario influenza viral surveillance data, and increasing influenza vaccination rates, with greater increases in Ontario than in other provinces combined. Respiratory antibiotic prescriptions are expressed as rate per 1000 people on the left vertical axis. Viral surveillance data (gray ‐ shaded areas) are expressed as the monthly percentage of positive test results on the right vertical axis. Vaccination rates for the household population aged 12 years (gray vertical bars, Ontario; black vertical bars, other provinces combined) are expressed as the percentage of the population vaccinated on the right vertical axis. The horizontal axis represents time. The black vertical line represents the introduction of the universal influenza immunization program (UIIP). Kwong et al CLIN INFECT DIS 2009 49(5):750-756.

16. Dose ‐ response relationship between change in respiratory antibiotic prescriptions and influenza vaccination rate. The vertical axis represents the pre ‐ /post ‐ 2000 relative rates for respiratory antibiotic prescriptions. The horizontal axis represents the absolute change in influenza vaccination rate for the household population aged 12 years from 1996– 1997 to the mean during the post ‐ 2000 period. Bubble size represents the inverse of the variance of the estimate of relative rate, used as the weighting factor in the weighted linear regression analysis. The solid line represents the weighted linear regression line, and the P value is for the regression coefficient. BC, British Columbia. Kwong et al. CLIN INFECT DIS 2009 49(5):750-756.

17. Dayton Daily News 09/01/2011

18. CDC. MMWR. February 15, 2008 / 57(06);144-148

19. Fact: Catheters and other invasive devices are the # 1 exogenous cause of hospital-onset infections. Prevent Infection Step 2: Get the catheters out

20. Biofilm on Intravenous Catheter Connecter 24 hours after Insertion Scanning Electron Micrograph

21. Process of Catheter Related Infections From the Quality and Safety Research Group Johns Hopkins University 2009

22. Risk Factors for catheter-related bloodstream infection Multiple lumen catheters- – increased tissue trauma predisposes to potential infection – more manipulation and contamination of multiple ports/hubs Total parenteral nutrition and/or lipid infusions Low nurse to patient ratio Site of insertion; subclavian vein poses less risk than internal jugular or femoral vein Merrer et al. JAMA. 2001;286:700- 7

23. Evidence based steps to preventing catheter-related bloodstream infections Clean hands (waterless alcohol based hand sanitizer or wash hands with soap and water)! Select best insertion site Use proper skin preparation (chlorhexidine) Use maximal barrier precautions Remove catheter as soon as possible

24. Fact: Appropriate antimicrobial therapy (correct regimen, timing, dosage, route, and duration) saves lives. Diagnose & Treat Infection Effectively Step 3: Target the pathogen

25. Fact: Appropriate antimicrobial therapy saves lives. Actions: culture the patient target empiric therapy to likely pathogens and local antibiogram target definitive therapy to known pathogens and antimicrobial susceptibility test results MDROs = microorganisms, predominantly bacteria, that are resistant to one or more classes of antibiotics. These pathogens are frequently resistant to most available antimicrobial agents Diagnose & Treat Infection Effectively Step 3: Target the pathogen

26. Organisms that can effectively “escape” the effects of antibacterial drugs E nterobacter S taphylococcus aureus K lebsiella A cinetobacter P seudomonas aeruginosa E nterococcus IDSA. Clin Infect Dis 2009;48 (1 January)

27. Causative agents with 3-class and 4-class antimicrobial resistance within infection types (National Healthcare Safety Network, 2006-2007) Kallen et al. Infect Control Hosp Epidemiol 2010;31:528–531

28. Giske et al. Antimicrobial Agents and Chemotherapy 2008; 52(3): 813-21.

29. Fact: Programs to improve antimicrobial use are effective – antibiotic stewardship Use Antimicrobials Wisely Step 5: Practice antimicrobial control

30. Associations between antimicrobial use and the emergence of antimicrobial resistance Changes in antimicrobial use are paralleled by changes in the prevalence of resistance. Antimicrobial resistance is more prevalent in healthcare-associated bacterial infections, compared with those acquired in the community. Patients with healthcare-associated infections caused by resistant strains are more likely than control patients to have received prior antibiotics. Areas within hospitals that have the highest rates of antimicrobial resistance also have the highest rates of antimicrobial use. Increasing duration of patient exposure to antimicrobials increases the likelihood of colonization with resistant organisms. IDSA and SHEA Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship Clin Infect Dis 2007; 44:159-77

31. Annual prevalence of imipenem resistance in P. aeruginosa vs. carbapenem use rate Gould et al. ICHE 2006;27:923-5

32. Mechanisms for the appearance or spread of antimicrobial resistance in hospital organisms Introduction of a resistant organism to a susceptible population Acquisition of resistance by a susceptible strain – Spontaneous mutation – Genetic transfer Expression of a regulated resistance already present in the population Selection of a resistant subpopulation Dissemination or spread of resistant organisms Clin Infect Dis 1997; 25:584-99 32

33. Infectious Disease Society of America (IDSA) Society for Healthcare Epidemiology of America (SHEA) CID 2007:44 159-177

34. Antibiotic stewardship: methods to control antimicrobial use to prevent or control antimicrobial resistance Optimal use of all antimicrobials (e.g., incorporate practice guidelines) Selective removal, control, or restriction of antimicrobial agents or classes Rotational or cyclic antimicrobial utilization Use of combination antimicrobial therapy to prevent the emergence of resistance Formulary restriction Intravenous to oral switch Automatic stop orders Computerized order entry Provider education (best when used with other interventions)

35. Ten Strategies proposed by IDSA and SHEA for implementation of an Antibiotic Stewardship (AS) Program 1. Prospective audit with intervention and feedback (A-I) 2. Formulary restriction and pre-authorization (A-II) 3. Education with intervention (A-III) 4. Guidelines with clinical pathways (A-III) 5. Antimicrobial cycling (C-II) 6. Antimicrobial order forms (B-II) 7. Reducing combination therapy (C-II) 8. Streamlining and de-escalation therapy (A-II) 9. Dose optimization (A-II) 10. Parenteral or oral conversion (A-III)

36. Carbapenem-resistant Pseudomonas aeruginosa and carbapenem utilization Lepper et al. AAC 2002;46:2920-5

38. Winter antibiotic prescriptions, France by region, October 2000 to March 2007 From 2001 to 2006, a decreasing trend was observed in the rate of pneumococci resistant to penicillin (47% to 32% of isolates) and the rate of pneumococci resistant to macrolides (49% to 36%) Sabuncu et al. PLoS Med. 2009 June; 6(6): e1000084 (Epub)

41. Fact:The prevalence of resistance can vary by time, locale, patient population, hospital unit, and length of stay. Use Antimicrobials Wisely Step 6: Use local data

42. Methicillin -resistant Staphylococcus aureus DCMC Percent Resistant

43. Surveillance as a strategy to prevent the spread of MDROs Active surveillance to identify patients colonized but not overtly infected with MDROs – Specimens from body sites can be submitted for culture – By identifying these individuals, measures can be taken to prevent the spread to other patients. – Active surveillance has been shown to reduce the frequency of MDRO infection in specific populations in a wide variety of settings.

44. CDC. MMWR 2009;58:256- 258

45. Fact:A major cause of antimicrobial overuse is “treatment” of contaminated cultures. Use Antimicrobials Wisely Step 7: Treat infection,not contamination

46. Mean blood culture contamination rate 1.9%. For ~600 children per quarter who had a blood draw from the lab personnel, 12 had a contaminated blood culture. DCMC Microbiology Laboratory

47. Mean blood culture contamination rate decreased from 3.3% to 1.4% 2001-2009. The number of children with a contaminated blood culture was reduced from 236 to 103 (7130 blood cultures per year total). That’s 133 children spared repeat visits, admissions, prolonged stays, excess charges and potential hospital acquired infections by undergoing further evaluations or being admitted unnecessarily. DCMC Microbiology Laboratory

48. Fact: Vancomycin overuse promotes emergence, selection, and spread of resistant pathogens. Use Antimicrobials Wisely Step 9: Know when to say “no” to vancomycin

49. S. aureus Penicillin [1950s] Penicillin-resistant S. aureus Evolution of Drug Resistance in S. aureus Methicillin [1970s] Methicillin-resistant S. aureus (MRSA) Vancomycin-resistant enterococci (VRE) Vancomycin [1990s] [1997] Vancomycin intermediate- resistant S. aureus (VISA) [ 2002 ] Vancomycin- resistant S. aureus

50. Bonten, M. J. M. et al. Arch Intern Med 1998;158:1127-1132. “Colonization pressure” in the spread of vancomycin-resistant enterococcus

51. Fact:Failure to stop unnecessary antimicrobial treatment contributes to overuse and resistance. Actions: when infection is cured when cultures are negative and infection is unlikely when infection is not diagnosed Use Antimicrobials Wisely Step 10: Stop antimicrobial treatment

52. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis Costelloe C et al. BMJ. 2010;340:c2096.

54. Prevent Transmission Step 11: Isolate the pathogen Fact:Patient-to-patient spread of pathogens can be prevented. Actions: use standard infection control precautions contain infectious body fluids (use approved airborne/droplet/contact isolation precautions) when in doubt, consult infection control experts

55. Isolation precautions to prevent the spread of MDROs The use of gowns and gloves when in a patient room is the standard of care for preventing transmission from patients with MDROs – Compliance is always an ongoing challenge! – Personal protective equipment (PPE) utilized prior to entering the room and removed prior to leaving the room. – Special contact isolation with MDROs

57. http://www.who.int/gpsc/country_work/hhsa_framework.pdf

58. Environmental hygiene to minimize the spread of MDROs Targeted to eliminate the reservoir of MDROs on hospital surfaces and equipment – MDROs can persist in the environment despite routine cleaning practices – Some resistant organisms can remain for weeks without proper surface disinfection – Patients admitted to rooms previously occupied by a patient with an MDRO are at higher risk for developing infection with that organism.

59. Decolonization to prevent the spread of MDROs Aims to eradicate resistant bacteria from colonized patients in an effort to prevent subsequent infection or spread – Topical antibiotics are often utilized – Limited experience in the use of decolonization in general hospital patients – Current guidelines, citing concern for the development of resistance to the drugs used for decolonization, advise against widespread use of this practice

60. Prevent Transmission Step 12: Break the chain of contagion Fact:Healthcare personnel can spread antimicrobial- resistant pathogens from patient to patient. Actions: stay home when you are sick contain your contagion keep your hands clean set an example!

62. The New York Times February 26, 2010

63. The β-lactam family of antibiotics Ceftriaxone 3 rd Ticarcillin Ceftazidime 3 rd Mezlocillin Cefotaxime 3 rd Carbenicillin Ertapenem Cefmetazole Cefuroxime 2 nd Ampicillin Meropenem Cefotetan Cefamandole 2 nd Methicillin AztreonamImipenemCefoxitinCephalothin 1 st Benzyl- penicillin MonobactamsCarbapenemsCephamycinsCephalosporinsPenicillins Cefepime 4 th Doripenem

64. The β-lactam family of antibiotics Ceftriaxone 3 rd Ticarcillin Ceftazidime 3 rd Mezlocillin Cefotaxime 3 rd Carbenicillin Ertapenem Cefmetazole Cefuroxime 2 nd Ampicillin Meropenem Cefotetan Cefamandole 2 nd Methicillin AztreonamImipenemCefoxitinCephalothin 1 st Benzyl- penicillin MonobactamsCarbapenemsCephamycinsCephalosporinsPenicillins Cefepime 4 th ESBLs hydrolyze all Penicillins Cephalosporins Monobactams Doripenem

65. The β-lactam family of antibiotics Ceftriaxone 3 rd Ticarcillin Ceftazidime 3 rd Mezlocillin Cefotaxime 3 rd Carbenicillin Ertapenem Cefmetazole Cefuroxime 2 nd Ampicillin Meropenem Cefotetan Cefamandole 2 nd Methicillin AztreonamImipenemCefoxitinCephalothin 1 st Benzyl- penicillin MonobactamsCarbapenemsCephamycinsCephalosporinsPenicillins Cefepime 4 th ampCs hydrolyze all Penicillins Cephalosporins except 4 th generation (cefepime) Cephamycins Monobactams Doripenem

66. The β-lactam family of antibiotics Ceftriaxone 3 rd Ticarcillin Ceftazidime 3 rd Mezlocillin Cefotaxime 3 rd Carbenicillin Ertapenem Cefmetazole Cefuroxime 2 nd Ampicillin Meropenem Cefotetan Cefamandole 2 nd Methicillin AztreonamImipenemCefoxitinCephalothin 1 st Benzyl- penicillin MonobactamsCarbapenemsCephamycinsCephalosporinsPenicillins Cefepime 4 th Metallo BL hydrolyze all Penicillins Cephalosporins Cephamycins Carbapenems Doripenem

67. The β-lactam family of antibiotics Ceftriaxone 3 rd Ticarcillin Ceftazidime 3 rd Mezlocillin Cefotaxime 3 rd Carbenicillin Ertapenem Cefmetazole Cefuroxime 2 nd Ampicillin Meropenem Cefotetan Cefamandole 2 nd Methicillin AztreonamImipenemCefoxitinCephalothin 1 st Benzyl- penicillin MonobactamsCarbapenemsCephamycinsCephalosporinsPenicillins Cefepime 4 th KPCs hydrolyze all Penicillins Cephalosporins Cephamycins Carbapenems Monobactams Doripenem

68. CMAJ October 2010

69. Conclusions: Key Prevention Strategies  Prevent infection  Diagnose and treat infection effectively  Use antimicrobials wisely  Prevent transmission  Education

70. “Mankind faces a crossroads. One path leads to despair and utter hopelessness, the other to total extinction.” Woody Allen

71. Sumo wrestling students hold babies as they try to make them cry during the Crying Sumo competition at Sensoji Temple on April 28, 2007 in Tokyo, Japan. The first baby to cry wins the competition. The ceremony takes place in Japan to wish for the good health of the child as it is said that crying is good for the health of babies. April 29, 2007 - Photo by Junko Kimura/Getty Images News