5/4/2018. Multidrug Resistant Organisms (MDROs) Objectives. Outline. Define a multi-drug resistant organism (MDRO)

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1 Multidrug Resistant Organisms (MDROs) Kasturi Shrestha, M.D. 05/11/2018 Objectives Define a multi-drug resistant organism (MDRO) Identify most challenging MDROs in healthcare Identify reasons for health concern Describe selection pressure and how antibiotic resistance spreads Summarize prevention strategies for acute and long-term care facilities Outline MDROs MRSA Definition VRE Prevalence Outcomes ESBLs Risk Factors CRE CDC Alerts Summary of Prevention Strategies Selection Pressure For Acute and Long-Term Care Mechanism, Transmission, and Spread Facilities of Resistance Four Core Actions to Fight Resistance MDR Pseudomonas aeruginosa 1

2 Definition For epidemiologic purposes, MDROs are defined as microorganisms, predominantly bacteria, that are resistant to one or more classes of antimicrobial agents. Although the names of certain MDROs describe resistance to only one agent (e.g., MRSA, VRE), these pathogens are frequently resistant to most available antimicrobial agents the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted. - Sir Alexander Fleming, June Session 1 Resistance in The United States 2

3 Reasons for concern Higher morbidity, mortality, and cost. Receive prolonged courses of antibiotic therapy. Require the use of more costly antibiotics. Have longer hospital stays. Require more frequent medical follow-up. Each occurrence of a bloodstream infection caused by ESBL Enterobacteriaceae adds over $40,000 in US Hospital costs. Risk Factors For Infections With MRDOs Recent receipt of antimicrobials. (USE/OVERUSE/MISUSE) Immunosuppressed state and chronic diseases and inflammatory conditions. Older age and lower functional status. Undergoing hemodialysis, surgery, and/or other invasive procedures. Presence of indwelling devices. Hospitalization or living in a long-term care facility. MDRO Alerts The Centers for Disease Control and Prevention, 2013: Urgent threats: Clostridium difficile Carbapenem Resistant Enterobacteriaceae (Klebsiella pneumonia, Escherichia coli, Enterobacter, Serratia, Proteus, Providencia, Morganella) Drug-resistant Neisseria gonorrheae Serious threats: Multidrug resistant Acinetobacter and MDR Pseudomonas aeruginosa Drug resistant Campylobacter, nontyphoid Salmonella, Salmonella typhi, Shigella, Streptococcus pneumoniae, tuberculosis Fluconazole resistant Candida ESBLs VRE MRSA Concerning threats: Vancomycin-resistant staphylococcus aureus Erythromycin resistant group A streptococcus Clindamycin resistant group B streptococcus 3

4 Selection Pressure Mechanisms of Transmission of Resistance Genes Common mechanisms Enzymatic alteration Change in target Efflux pumps Decreased permeability (e.g., porin mutations) Plasmids Circular extrachromosomal DNA Can be transferred to other bacteria via conjugation 4

5 Are all MDROs spread in the same way? Most MDROs are transmitted from patient to patient via hands of healthcare workers Also spread via objects such as medication cart handles, bed rails, bedside tables, IV poles Direct contact (e.g., touching an oozing sore) Four Core Actions to Fight Resistance. 5

6 Four Core Actions to Fight Resistance. Four Core Actions to Fight Resistance. Four Core Actions to Fight Resistance. 6

7 Infection Control Precautions to Prevent Transmission of MDROs Follow Standard Precautions during all patient encounters in all settings in which healthcare is delivered. Use masks according to Standard Precautions when performing splashgenerating procedures (e.g., wound irrigation, oral suctioning, intubation); when caring for patients with open tracheostomies and the potential for projectile secretions; and in circumstances where there is evidence of transmission from heavily colonized sources (e.g., burn wounds). Masks are not otherwise recommended for prevention of MDRO transmission from patients to healthcare personnel during routine care (e.g., upon room entry). Implement Contact Precautions routinely for all patients infected with target MDROs and for patients that have been previously identified as being colonized with target MDROs (e.g., patients transferred from other units or facilities who are known to be colonized). MRSA Staphylococcus aureus developed resistance to penicillin in the late 1940s and throughout the 1950s Methicillin was introduced to counter this resistance problem In 1961 the first strains of MRSA were identified in Britain 1968 the first US human case of MRSA MRSA is resistant to all beta-lactams An important cause of serious infections in the community Can colonize the skin and subsequently cause infections ranging from simple skin and soft tissue infections to prosthetic device and severe bloodstream infections Intermediately susceptible and resistant to vancomycin (VISA, VRSA) MICs: 2, 4-8, 16 Daptomycin, linezolid, ceftaroline, dalbavancin 7

8 Vancomycin Resistance S. aureus CoNS Enterococcus species Susceptible MIC 2 μg/ml 4 μg/ml 4 μg/ml Intermediate MIC 4-8 μg/ml (thickened cell wall) 8-16 μg/ml 8-16 μg/ml vanc encoded; intrinsic vancomycin resistance E. casseliflavus and E. Gallinarum Resistant MIC 16 μg/ml Very few isolates worldwide 32 μg/ml 32 μg/ml vana or vanb epidemiologically significant. Plasmid- or transposonmediated. VRE About 77% of E faecium isolates are resistant to vancomycin About 9% of E faecalis isolates are resistant to vancomycin Some strains of VRE retain susceptibility to ampicillin VRE 8

9 ESBL-producing Enterobacteriaceae Beta-lactamase Conferring Resistance. B-lactam drug group Examples Penicillinases ESBL AmpC Carbapenemase Penicillins Cephalosporins Penicillin Ampicillin Ceftazidime Ceftriaxone Cefotaxime X X X X X X X BL/BLI Amox/Clav X X Pip/Tazo Monobactams Aztreonam X X X Carbapenems Ertapenem Imipenem Doripenem Meropenem X E coli Amox/Clav S Ampicillin R Cefazolin Cipro R R Gentamicin R 9

10 Treatment Carbapenems, quinolones, sulfamethoxazole/trimethoprim, aminoglycosides, cefepime, fosfomycin Piperacillin/tazobactam Ceftolozane/tazobactam, Ceftazidime/avibactam Carbapenem-Resistant Enterobacteriaceae (CRE) In January 2015, The Centers for Disease Control and Prevention (CDC) modified its surveillance definition for CRE to the current definition (resistant to imipenem, meropenem, doripenem, or ertapenem OR documentation that the isolate possess a carbapenemase). Modified Hodge test, mass spectrometric detection, PCR assays, DNA microassays. Carbapenem-Resistant Enterobacteriaceae (CRE) Two mechanisms of carbapenem resistance - Carbapenemase (B-lactamase that hydrolyzes carbapenems) - Cephalosporinase combined with porin loss Some cephalosporinases (eg, AmpC-type B-lactamases or certain ESBLs, eg, CTX-M) have low-level carbapenemase activity Porin loss limits entry of carbapenem into periplasmic space 10

11 CRE Gram-Negative Beta-lactamase Summary Beta-lactamase Example Enzymes Antibiotics That Are Inactivated Broad-spectrum TEM-1, TEM-2, SHV-1 Penicillins (penicillin, amoxicillin, ampicillin, piperacillin) Narrow-spectrum cephalosporins (cefazolin, cefuroxime) OXA family As above plus cloxacillin, oxacillin Extended-spectrum TEM and SHV families Substrates of broad-spectrum group plus cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, aztreonam CTX-M family Above plus cefepime for some OXA family AmpC Carbapenemase SPICE: Serratia sp., Providencia sp., "Indole-positive" Proteus sp., Citrobacter sp., and Enterobacter sp. Metallo-B-lactamases - IMP, VIM, GIM, SPM, NDM KPC Oxa-48-like Substrates of expanded-spectrum group plus cefoxitin, cefotetan (other cephamycins) Substrates of ertapenem, imipenem, meropenem, doripenem CRE Susceptibility testing is vital to guide antimicrobial therapy Quinolones, SMX/TMP Ceftazidime/avibactam (not NDM) Polymyxins Aminoglycosides Tigecycline Fosfomycin 11

12 Summary of Prevention Strategies For Acute and Long-Term Care Facilities. 1. Hand Hygiene Promote hand hygiene No recommendations for discontinuation of CP Acute Care Monitor hand hygiene adherence and provide feedback Place CRE colonized or infected patients on Contact Precautions (CP) Ensure access to hand hygiene stations o Empiric CP might be used for patients 2. Contact Precautions (CP) transferred from high- risk settings Educate and train healthcare personnel Long-term Care about CP including allowing time to practice donning and doffing Place CRE colonized or infected residents that are high-risk for transmission on CP; for Monitor CP adherence and provide feedback patients at lower risk for transmission use precautions based on type of care provided Summary of Prevention Strategies For Acute and Long-Term Care Facilities. 3. Healthcare Personnel Education 4. Minimize Use of Invasive Devices 5. Timely Notification from Laboratory When CRE are Identified 6. Communication of CRE Status for Infected and Colonized Patients at Discharge and Transfer Identify known CRE patients at re-admission 7. Promotion of Antimicrobial Stewardship 8. Environmental Cleaning 9. Patient and Staff Cohorting and the staff that care for them even if patients are housed in single rooms 10. Screening Contacts of CRE Patients Screen patient with epidemiologic links to unrecognized CRE colonized or infected patients 11. Active Surveillance Testing Screen high-risk patients at admission or at admission and periodically during their facility stay for CRE. Empiric CP can be considered while results of admission surveillance testing are pending 12. Chlorhexidine Bathing Bathe patients with 2% chlorhexidine When available cohort CRE colonized or infected patients Question Which of the following susceptibility patterns would be typical for a Klebsiella pneumoniae isolate which carries a carbapenemase? Cefazolin Cefotaxime Ceftazidime Pip/tazo Imipenem Aztreonam a) R S S S S S b) R R R S S R c) R R R R S R d) R R R R R R 12

13 Question Which of the following susceptibility patterns would be typical for an Escherichia coli isolate carrying a New Delhi metallo--lactamase (NDM)? Cefazolin Cefotaxime Ceftazidime Pip/tazo Imipenem Aztreonam a) R S S S S S b) R R R S S R c) R R R R S R d) R R R R R R Question Which of the following susceptibility patterns would be typical for an Escherichia coli isolate producing an extended spectrum -lactamase? Cefazolin Cefotaxime Ceftazidime Pip/tazo Imipenem Aztreonam a) R S S S S S b) R R R S S R c) R R R R S R d) R R R R R R Question A patient has Escherichia coli bacteremia. Prior to the availability of phenotypic susceptibility results, the laboratory reports that the E. coli isolate tests positive by PCR for a CTX-M gene, which encodes an extended-spectrum β-lactamase. Which of the following is most likely to be active against this organism? a) Ceftazidime b) Ceftriaxone c) Aztreonam d) Cefepime e) Meropenem 13

14 MDR PA Carbapenem Resistant Pseudomonas aeruginosa Healthcare associated infections: Pneumonia, bacteremia, surgical site infection, UTIs, wound infection Carbapenem resistance from % Serine-based carbapenemase: ceftazidime/avibactam, meropenem/vaborbactam Metallo-carbapenemase: ceftazidime/avibactam + aztreonam; polymyxin Efflux pumps: susceptibility testing Decrease in cell wall permeability Pseudomonas aeruginosa Cefepime R Ciprofloxacin R Gentamicin I Meropenem R Pip/Tazo R Tobra S 14

15 MDR PA Fluoroquinolones Aminoglycosides Piperacillin/tazobactam: Inoculum effect Cefepime, ceftazidime Ceftolozane/tazobactam Cefatazidime/avibactam General principles and recommendations Prevent infections and spread of resistance Performed good hand hygiene practices Avoid the use of indwelling devices without a clear indication Place patients with known MDRO infections or with positive surveillance cultures on contact isolation to prevent transmission Track resistance pathogens Implement and support hospital and global surveillance programs of resistant pathogens Improve the use of antibiotics Avoid administering unnecessary antimicrobials Choose narrow spectrum antimicrobials when possible Implement antimicrobial stewardship programs Seek guidance from infectious disease specialists Support development of new antimicrobials and diagnostic test for resistant microorganisms Handwashing Wet your hands with clean, running water (warm or cold), turn off the tap, and apply soap. Lather your hands by rubbing them together with the soap. Be sure to lather the backs of your hands, between your fingers, and under your nails. Scrub your hands for at least 20 seconds. Need a timer? Hum the Happy Birthday song from beginning to end twice. Rinse your hands well under clean, running water. Dry your hands using a clean towel or air dry them. 15

16 THANK YOU. References: Facility Guidance for Control of Carbapenem-resistant Enterobacteriaceae (CRE) November 2015 Update CRE Toolkit Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th Edition 16