Antibiotic Resistant Pathogens in the Health Care Setting

1. Antibiotic Resistant Pathogens in the Health Care Setting Focus On Infection Control VA APIC Conference 2005 Gonzalo Bearman MD, MPHAssistant Professor of Medicine, Epidemiology and Community HealthAssociate Hospital EpidemiologistVirginia Commonwealth University

2. Outline • Nosocomial Infections • Background, Epidemiology • Changing Paradigm • Important Nosocomial Pathogens • MRSA • CA MRSA • VRE • MDR- GNRs • ESBL producing organisms • C.difficile • Importance of hand hygiene in decreasing cross transmission • Alcohol based hand sanitizers • Isolation Categories • Contact Isolation • Gowns and gloves • Compliance with IC guideline • The importance of process measure feedback

3. Nosocomial Infections • 5-10% of patients admitted to acute care hospitals acquire infections • 2 million patients/year • ¼ of nosocomial infections occur in ICUs • 90,000 deaths/year • Attributable annual cost: $4.5 – $5.7 billion • Cost is largely borne by the healthcare facility not 3rd party payors Weinstein RA. Emerg Infect Dis 1998;4:416-420. Jarvis WR. Emerg Infect Dis 2001;7:170-173.

4. Major Sites of Nosocomial Infections • Urinary tract infection • Surgical site infection • Bloodstream infection • Pneumonia (ventilator-associated)

5. Nosocomial Infections • 70% are due to antibiotic-resistant organisms • Invasive devices are more important than underlying diseases in determining susceptibility to nosocomial infection Burke JP. New Engl J Med 2003;348:651-656. Safdar N et al. Current Infect Dis Reports 2001;3:487-495.

6. Nosocomial Infections in the US Burke JP. New Engl J Med 2003;348:651-656.

7. Attributable Costs of Nosocomial Infections Nettleman M. In: Wenzel RP, ed. Prevention and Control of Nosocomial Infections, 4th ed. 2003:36.

8. Shifting Vantage Points on Nosocomial Infections Many infections are inevitable, although some can be prevented Each infection is potentially preventable unless proven otherwise Gerberding JL. Ann Intern Med 2002;137:665-670.

9. Antibiotic Resistant Pathogens in the Hospital Setting

10. NNIS Summary 2004 Fig 1. Selected antimicrobial-resistant pathogens associated with nosocomial infections in ICU patients, comparison of resistance rates from January through December 2003 with 1998 through 2002, NNIS System. CNS, Coagulase-negative staphylococci; 3rd Ceph, resistance to 3rd generation cephalosporins (either ceftriaxone, cefotaxime, or ceftazidime); Quinolone, resistance to either ciprofoxacin or ofloxacin. Percent (%) increase in resistance rate of current year (January-December 2003) compared with mean rate of resistance over previous 5 years (1998-2002): [(2003 rate – previous 5-year mean rate)/previous 5-year mean rate] × 100. American Journal of Infection ControlVolume 32, Issue 8 , December 2004, Pages 470-485

11. MRSA (Methicillin Resistant S.aureus) • Appeared in 1980s • 50-70% of hospital S.aureus isolates are MRSA • Carrier state (colonization)- asymptomatic • Reduce transmission by detecting and treating all infected and colonized patients • Drug of choice is vancomycin • Patients with MRSA infection/colonization are placed on contact isolation • Recent reports of a vancomycin resistant strains of S.aureus • Certain to be an increasingly difficult management problem

12. Methicillin-resistant–Staphylococcus aureus Hospitalizations, United States • National Hospital Discharge Survey used to calculate the number of US hospital discharges listing S. aureus–specific diagnoses • From 1999 to 2000: • 125,969 hospitalizations with a diagnosis of MRSA infection occurred annually • 31,440 for septicemia (BSI) • 29,823 for pneumonia • 64,706 for other infections • 3.95 per 1,000 hospital discharges • National burden of serious MRSA disease is substantial Kuehnert MJ, Hill HA, Kupronis BA, Tokars JI, Solomon SL, Jernigan DB. Methicillin-resistant–Staphylococcus aureus Hospitalizations, United States. Emerg Infect Dis [serial on the Internet]. 2005 Jun. Available from http://www.cdc.gov/ncidod/EID/vol11no06/04-0831.htm

13. Community Acquired MRSA

14. VRE (vancomycin resistant enterococci) • Enterococcus faecalis and E. faecium • E. faecium is the most frequently isolated species of VRE in hospitals and typically produces high vancomycin (>128 µg/ml) and teicoplanin (>16 µg/ml) minimum inhibitory concentrations (MICs) • Normal inhabitants of bowel • Can cause UTI, BSI, VAP and wound infections in critically ill patients • Cross infection via contaminated equipment documented • Thermometers

15. MRSA and VRE • Prevention of MRSA/VRE infections is based upon standard infection control precautions including: • Hand Washing • Wash hands immediately after gloves are removed, between patient contacts and between tasks and procedures. • Gloving – contact isolation • Wear gloves when touching blood, body fluids and contaminated items • Remove gloves between patient contacts and wash hands immediately. • Gowning –contact isolation • Wear a gown during procedures that are likely to generate splashes or droplets of blood and body fluids. • Dedicated Patient Care Equipment • Appropriate cleaning, disinfection and sterilization of patient care equipment are important in limiting the transmission of organisms.

16. MDR Gram Negative Rods • MDR gram negative rods are defined as isolates that are susceptible to no more than one class of antimicrobial agents (excluding colistin). • Increasingly problematic • Acinetobacter baumanii • Stenotrophomonas maltophilia • Pseudomonas aeruginosa

17. Application of control measures for infections caused by multi-resistant gram-negative bacteria in intensive care unit patients • Prospective study of ICU patients in the Hospital Sao Paulo, between March-June 1997 and March-June 1998. • Surveyed nosocomial infections with multi-resistant microorganisms: • A.baumannii and P.aeruginosa: resistant to : aminoglycosides, quinolones, third-generation cephalosporins, and carbapenems. Mem. Inst. Oswaldo Cruz vol.99 no.3 Rio de Janeiro May 2004

18. Application of control measures for infections caused by multi-resistant gram-negative bacteria in intensive care unit patients Promotion of hand hygiene (PVP-I or chlorexidine) before and after contact with the patient Application of contact isolation measures Daily surface cleaning and disinfection with alcohol at 70% Separation of articles and equipment for exclusive use of the patient Study showed significant increase in percentage of multi-resistant pathogens in second period vs first period UTI with multi-resistant increased from 22.7% to 30%, pneumonia 8.3% to 33.3% , and in BSI from 4.7% to 60% Infections with MDR GNR are difficult to manage and will likely require more than just stringent IC practice Mem. Inst. Oswaldo Cruz vol.99 no.3 Rio de Janeiro May 2004

19. RelativelyPoorOutcomeafterTreatmentofClostridiumdifficileColitiswithMetronidazoleRelativelyPoorOutcomeafterTreatmentofClostridiumdifficileColitiswithMetronidazole Prospective,observational study of 207patients who were treatedwith metronidazole for C. difficilecolitis • 103patients (50%) were curedby the initial courseof therapy and hadno recurrence of disease. • 22% continuedto have symptoms ofcolitis for 10 daysdespite treatment • 28% responded initially buthad a recurrence withinthe ensuing 90 days. • The mortality rate higher amongpatients who did notrespond fully to aninitial course of therapy,compared with those whodid (33% vs. 21%;P < .05) Clinical Infectious Diseases    2005;40:1586-1590

20. IncreasingRiskofRelapseafterTreatmentofClostridiumdifficileColitis inQuebec,Canada Kaplan-Meier plots of the60-day probabilities of recurrenceamong patients with Clostridium difficile associateddiarrhea treated with onlymetronidazole, comparing 1991-2002 to2003-2004 (top). Treatment with onlyvancomycin during 1991 2002 to 2003-2004 (bottom) Clinical Infectious Diseases    2005;40:1591-1597

21. Clostridiumdifficile • Because ofthe increasingly poor responseto therapy, additional approachesto prevention and/or treatmentof C. difficile colitis are in order • Newer therapies • nitazoxanide or tinidazole • probiotics, such as Saccharomyces boulardiiand Lactobacillus species • Stringent application of infection control measures • Contact isolation • Meticulous hand hygiene • Thorough terminal disinfection of patient rooms • (sporicidal agent)

22. The ABC’s of ESBL for Infection Control Nurses: -Extended-Spectrum Beta-Lactamases-

23. Epidemiology • Today, 30 – 50% of E. coli are resistant to ampicillin and amoxicillin due to a beta-lactamase • ESBLs have been reported for E.coli, Klebsiella, Enterobacter, Proteus,Pseudomonas, Salmonella, Serratia

24. Beta-Lactamases: What are they ? • Enzymes produced by certain bacteria that provide resistance to certain antibiotics • Produced by both gram positive and gram negative bacteria • Found on both chromosomes and plasmids

25. Beta-lactamases • Are primary mode of resistance to beta-lactam antibiotics • Produced by some gram positive bacteria and virtually all gram negative bacteria

26. ESBL? • Resistance that is produced through the actions of beta-lactamases. • Extended spectrum cephalosporins, such as the third generation cephalosporins, were originally thought to be resistant to hydrolysis by beta-lactamases! • Not so! • mid 1980's it became evident that a new type of beta-lactamase was being produced by Klebsiella & E coli that could hydrolyze the extended spectrum cephalosporins. • These are collectively termed the • 'extended spectrum beta-lactamases' (ESBL's)

27. Mechanism of Action • Hydrolysis of beta-lactam ring of basic penicillin structure • Hydrolysis = adding a molecule of H2O to C-N bond with enzyme action • This opens up the ring, thus making the drug ineffective!

28. Plasmids • Rings of extrachromosomal DNA • Can be transferred between different species of bacteria conjugation • Carry resistance genes • Most common and effective mechanism of spreading resistance from bacteria to bacteria Bacterial Conjugation

29. Beta-lactam Antibiotic Examples • Penicillins: • Penicillin, amoxicillin, ampicillin • Cephalosporins: • Ancef, Rocephin, Keflex, Cefotan • Carbapenems: • Imipenem, meropenem

30. Beta-lactamase inhibitor • Clavulanic acid + amoxicillin = Augmentin • Clav. Acid + ticarcillin = Timentin • Sulbactam + ampicillin = Unasyn • Tazobactam + piperacillin = Zosyn Good News:Beta-lactamase inhibitors inhibit the beta lactamase thereby not allowing the molecule to hydrolyze the antibiotic. Most ESBLS remain susceptible to Beta-lactamase inhibitors Bad News:some ESBL producing bacteria produce large amounts of beta-lactamase thereby overwhelming the beta-lactamase inhibitors

31. The story is more complicated…. • Multiple antimicrobial resistance is often a characteristic of ESBL producing gram-negative bacteria. • Ceftazidime • Cefotaxime • Ceftriaxone • Aztreonam • Genes encoding for ESBLs are frequently located on plasmids that also carry resistance genes for: • Aminoglycosides • Tetracycline • TMP-SULFA • Chloramphenicol • Fluoroquinolones

32. NCCLS ESBL Screening • For isolates: • K.pneumoniae, E.coli and K.oxytoca : • 1st step- screen using: • Ceftazidime, ceftriaxone, cefotaxime, cefpodoxime, or aztreaonam • 2nd Step: If MIC> 2 mcg/ml then: • Ceftazidime and cefotaxime alone and in combination with clavulanate • Positive test: greater than a three-fold reduction in MIC for combination versus single agent • ESBL status of organism is now highly likely

33. Take home message: ESBLs are harbingers of multidrug resistance

34. What are the clinical implications? • Can result in treatment failure • Morbidity and mortality • Several outbreaks have occurred • If an ESBL is detected, all penicillins, cephalosporins, and aztreonam should be reported as “resistant”, regardless of in vitro susceptibility test results

35. Management of ESBL infections • Pharmacotherapy: • Treatment of choice for serious infections • Carbapenems • Stable in the presence of most beta-lactamases • Examples • Imipenem • Meropenem • Restrict the use of 3rd generation cephalosporins.

36. Infection Control? As infection control nurses your job is to ensure that adequate precautions are taken to minimize the risk of cross transmission! • Contact precautions • Cohort patients during outbreaks • Promote meticulous hand hygiene practices • Reminders to HCW staff about Patient ESBL status • Electronic flagging of medical record • Placing stickers on charts • When are contact precautions discontinued? • No specific guidelines: • Resolution of infectious process

37. Nosocomial Drug Resistant Pathogens: • Nosocomial pathogens of continued or increasing concern • MRSA • CA-MRSA • VRE • C.difficile • MDR GNR • ESBL producing organisms

38. 30%-40% of all Nosocomial Infections are Attributed to Cross Transmission

39. The inanimate environment is a reservoir of pathogens X represents a positive Enterococcus culture The pathogens are ubiquitous ~ Contaminated surfaces increase cross-transmission ~ Abstract: The Risk of Hand and Glove Contamination after Contact with a VRE (+) Patient Environment. Hayden M, ICAAC, 2001, Chicago, IL.

40. The inanimate environment is a reservoir of pathogens Recovery of MRSA, VRE, C.diff CNS and GNR Devine et al. Journal of Hospital Infection. 2001;43;72-75 Lemmen et al Journal of Hospital Infection. 2004; 56:191-197 Trick et al. Arch Phy Med Rehabil Vol 83, July 2002 Walther et al. Biol Review, 2004:849-869

41. The inanimate environment is a reservoir of pathogens Recovery of MRSA, VRE, CNS. C.diff and GNR Devine et al. Journal of Hospital Infection. 2001;43;72-75 Lemmen et al Journal of Hospital Infection. 2004; 56:191-197 Trick et al. Arch Phy Med Rehabil Vol 83, July 2002 Walther et al. Biol Review, 2004:849-869

42. The inanimate environment is a reservoir of pathogens Recovery of MRSA, VRE, CNS. C.diff and GNR Devine et al. Journal of Hospital Infection. 2001;43;72-75 Lemmen et al Journal of Hospital Infection. 2004; 56:191-197 Trick et al. Arch Phy Med Rehabil Vol 83, July 2002 Walther et al. Biol Review, 2004:849-869

43. Transfer of VRE via HCW Hands • 16 transfers (10.6%) occurred in 151 opportunities. • 13 transfers occurred in rooms of unconscious patients who were unable to spontaneously touch their immediate environment Duckro et al. Archive of Int Med. Vol.165,2005

44. Alcohol Based Hand Sanitizers • CDC/SHEA hand antiseptic agents of choice • Recommended by CDC based on strong experimental,clinical, epidemiologic and microbiologic data • Antimicrobial superiority • Greater microbicidal effect • Prolonged residual effect • Ease of use and application

45. Alcohol based hand hygiene solutions Easy to use Quick Very effective antisepsis due to bactericidal properties of alcohol

46. Impact of alcohol based hand sanitizers at VCU: can this improve hand hygiene?

47. Study Algorithm Incremental Increase in Alcohol Dispensers Hand Hygiene Educational Program Implemented Direct Observation of Hand Hygiene Arch Intern Med. 2000;160:1017-1021.

48. Results Hand hygiene practice can be improved with education and greater accessibility of alcohol hand sanitizers • Improvement in Hand Hygiene Compliance Arch Intern Med. 2000;160:1017-1021.

49. Hand Hygiene • Single most important method to limit cross transmission of nosocomial pathogens • Multiple opportunities exist for HCW hand contamination • Direct patient care • Inanimate environment • Alcohol based hand sanitizers are ubiquitous • USE THEM BEFORE AND AFTER PATIENT CARE ACTIVITIES

50. Types of Isolation Precautions Transmission-based Precautions -for patients with documented or suspected infections -3 Types: airborne, droplet and contact • Standard Precautions • Apply to all Patients • -Replace Universal Precautions