CARBAPENEM RESISTANT ENTEROBACTERIACEAE (KPC CRE)

Bartsch SM et al. Potential economic burden of carbapenem-resistent Enterobacteriaceae (CRE) in the United States. Clin Microbiol Infect 2017;23(1):48e9-e16.

INDIANA CP-CRE CASES, 2016-2018 60 Total: 355 Total: 294 Total: 153 50 2016 2017 2018 Cases 40 30 20 Average: 27 10 0 Month *Preliminary 2018 data represents 1/1/2018 5/31/2018

INDIANA CP-CRE CASES BY DISTRICT, 2016-2018 State: 802 District 1: 358 District 2: 29 District 3: 62 District 4: 18 District 5: 176 District 6: 86 District 7: 40 District 8: 16 District 9: 17 District 10: 0 *Preliminary 2018 data represents 1/1/2018 5/31/2018

INDIANA CP-CRE CASES, 2016-2018 802 CP-CRE cases ORGANISMS 621 KLEBSIELLA PNEUMONIAE 55 SERRATIA MARCESCENS MECHANISMS 44 ESCHERICHIA COLI 740 KPC 36 ENTEROBACTER CLOACAE COMPLEX 18 NDM 18 CITROBACTER FREUNDII COMPLEX 15 VIM 14 KLEBSIELLA OXYTOCA 9 OXA-48-LIKE 6 CITROBACTER KOSERI 20 UNKNOWN 3 PROTEUS MIRABILIS 2 KLEBSIELLA AEROGENES 1 PROVIDENCIA RETTGERI 1 LECLERCIA ADECARBOXYLATA 1 MORGANELLA MORGANII *Preliminary 2018 data represents 1/1/2018 5/31/2018

1. 2. Most bacteria have 1 or 2 mechanisms of resistance. P. aeruginosa & Acinetobacter use ALL FOUR! 3. 4. 9

CRE Carbapenemase Producing (CP-CRE) Multiple Mechanisms KPC NDM VIM OXA SME IMI Porin Enzyme Efflux Ceftaz/avibactam Meropenem/ vaborbactam Polymixins Aztreonam Aztreonam PLUS Ceftaz/avibactam Polymixins

VICIOUS CYCLE Fluoroquinolones ES Cephalosporins ESBLs Tigecycline, Colistin Nursing Home LTAC Hemodialysis Carbapenem Use Carbapenemase

The selection of the optimal antimicrobial drug regimen, including dose, route, and duration of therapy Right Drug Right Dose Right Diagnosis Antimicrobial Stewardship Right Duration Barlam, TF et al. Guideline for Implementing an Antibiotic Stewardship Program, CID 2016

Leadership Commitment Hospital administration supports efforts to improve antimicrobial use Accountability Identify a single leader responsible for program outcomes Training in AMS Drug Expertise Identify a pharmacist to co-lead Action Develop interventions or policies to improve antibiotic use Tracking & Reporting Monitor prescribing patterns Report on antimicrobial use, patient outcomes, and resistance patterns Education Educate staff and patients about resistance and optimal prescribing CDC. Core Elements of Hospital Antibiotic Stewardship Programs. Atlanta, GA: US Department of Health and Human Services, CDC; 2014

AMS TEAM ID MD* ID PharmD* Information Technologist Infection Preventionist Patient Quality Improvement Clinicians Nurses Laboratory *Recommended to have specific training/expertise in antimicrobial stewardship

Formulary Management Education Combat the Emergence of Resistance Guidelines & Order Sets Dose Optimization Antimicrobial Stewardship De-escalation Length of Therapy Selection of Antimicrobial Control Costs Diagnosis Dellit TH. Clin Infect Dis 2007;44(2):159-77. Lawrence KL, et al. Am J Respir Crit Care Med 2009;179:434-438. Improve Clinical Outcomes Rapid Diagnostics & Microbiology IV to PO

1. 2. 3.

3 days 7 days 10 days 14 days 14-21 days 28 days 28-56 days Chastre J, et al. JAMA 2003; 290: 2588-98

STUDY DETAILS STUDY DESIGN OUTCOMES Stamm WE, et al. Acute renal infection in women: Treatment with TMP-SMX or Ampicillin for 2 or 6 Weeks Prospective, randomized trial 2 weeks of treatment was as efficacious as 6 weeks of treatment Longer duration was less well tolerated (more adverse effects) Longer duration was associated with increased recurrence (20% for 2 weeks and 36% for 6 weeks) Published 1987 Included 60 patients Treatment groups: Ampicillin PO or TMP/SMX PO Duration: 2 or 6 weeks Gupta K, et al. Clin Infect Dis 2011; 52(5): e103-e120. Stamm WE, et al. Ann Intern Med 1987; 106: 341.

Days of IV Vancomycin Therapy vs. VRE Infection Risk 1.5 1-3 days 3.2 4-7 days 5.4 >7 days None Also saw increased risk of VRE infection with use of fluoroquinolones and meropenem Antibiotics may drive resistance outside of their own class Gouliouris T et al. Duration of exposure of multiple antibiotics is associated with increased risk of VRE bacteremia: a nested case-control study. J Antimicrob Chemother 2018;73:1692-1699.

LARGE IMPACT

Redefining the Antibiotic Stewardship Team: Recommendations from the American Nurses Association/Centers for Disease Control and Prevention Workgroup on the Role of Registered Nurses in Hospital Antibiotic Stewardship Practices. 2017. CDC

If the answer is yes to all these questions, discussion about switching to oral antibiotics is appropriate

Early Switch Therapy Moderate to severe PNA LOS -3.34days 95%CI -4.42, -2.25 Adverse events OR 0.65 95%CI 0.48, 0.89 No difference in treatment success OR 0.92 95%CI 0.61, 1.39 No difference in Recurrence OR 1.81 95%CI 0.7, 4.72 No difference in Mortality OR 0.81 95%CI 0.49, 1.33 CAP (Meta of 3 studies) Mean LOS -3.04days 95%CI -4.9 to -1.19 Mandel LA, et al. CID 2007;44(suppl 2):S27-72.

ARE CULTURES REALLY THAT IMPORTANT TO ANTIMICROBIAL STEWARDSHIP? 31

IMPACT OF CULTURE RESULTS Need to Treat or Not Treat Drive Order Sets / Empiric Treatments Impact Quality Metrics (ie. CAUTI) Drug Selection Influence Drug Formulary Decisions Antibiotic Resistance Dose Selection Annual Antibiogram Report Patient Outcomes Duration of Treatment Isolation Precautions Cost of Care 32

WHY IS TECHNIQUE IMPORTANT? NEITHER REQUIRE ANTIBIOTICS! Normal Flora of the Skin Staphylococci (Coagulase-negative) Staphylococcus aureus Diphtheroids (corynebacterium) Streptococci sp. 33

KEYS TO SUCCESS 34

SWABS & SENDING SPECIMENS 35 (Adapted from Perry AG, et al. [2014]. Clinical nursing skills & techniques [8th ed]. St. Louis: Mosby.)

Microbiology Workflow Blood Drawn t=0 Gram Stain t=8 h Samples Plated for Sub-culture t=24-36h Resistance Testing Culture Results t=48-72h

COST OF MICROBIOLOGY LAB WORK-UP Deep wound culture performed $387* $900* 37 *Cost does not include tech time

~10% 95% of patients report a penicillin allergy are not allergic Sacco KA. Allergy 2017; 72:1288-1296

40 Vancomycin Cefazolin 35 30 25 % Patients 20 15 10 5 0 Treatment Failure(1) Mortality (2) 1. Stryjewski ME. Clin Infect Dis.2007;44:190-6. 2. Kim S. Antimicrob Agents Chemother.2008;52(1):192-197.

Study Details Study Design Results Clin Infect Dis 2016;63(7):904-910. Prospective, cohort study conducted on the ID service at 3 academic hospitals N=507 patients 95 (19%) had β-lactam allergies Beta-lactam was preferred therapy in 72 (76%) J Allergy Clin Immunol 2014;133:790-796. Retrospective, matched cohort study of patients admitted to Kaiser Foundation Hospitals 51,582 unique subjects with PCN allergy were casematched with 2 controls When β-lactam preferred, 25 (35%) did not receive preferred treatment, despite 13 (52%) reported as non-severe reactions Patients who did not receive preferred βlactam therapy had greater risk of adverse events (aor, 3.1; 95% CI, 1.28-7.89) vs those w/o allergy Patients receiving preferred β-lactam therapy had similar risk of adverse events vs those w/o allergy (aor, 1.33; 95% CI, 0.62-2.87) Cases w/ PCN allergy averaged 0.59 (9.9%; 95% ci, 0.47-0.71) more hospital days vs controls Cases were treated w/ more FQs, clindamycin, and vancomycin (P<0.0001) vs controls Cases had 23.4% (95% CI, 15.6% to 31.7%) more C.difficile, 14.1% (95% CI, 7.1% to 2`.6%) more MRSA, and 30.1% (95% CI, 12.5% to 50.4%) more VRE vs controls

Urticaria/Hives Wheezing Shortness of Breath Angioedema Anaphylaxis Stephen s Johnson Syndrome N/V (Intolerance) Headache (Intolerance) Diarrhea (Intolerance) Family History (not a true allergy) Known side effects of medications Additional Questions: How long ago was the reaction? What antibiotics have they tolerated since?

Odds Ratio of Receiving Carbapenem AMS intervention Prior B-lactam PCN allergy 0 0.5 1 1.5 2 Al-Hasan, MN, et al.pharmacotherap.2018,38(1):42-50. 2.5 3 3.5 4 4.5

MINIMUM INHIBITORY CONCENTRATION OR MIC S I R

Concentration Cmax:MIC AUC:MIC T>MIC MIC 0 Time (hours) AUC = Area under the concentration time curve Cmax = Maximum plasma concentration

Drug Time>MIC Susceptible (µg/ml) Piperacillin/ tazobactam 16 Ceftriaxone 1 Cefepime 8 Meropenem P. aeruginosa Peak:MIC Enterobacteriaceae 2 1 Tobramycin 4 Ciprofloxacin 1

Susceptible (µg/ml) Peak Serum Concentration (µg/ml) Piperacillin/ tazobactam 16 242 Ceftriaxone 1 150 Cefepime 8 164 Drug Time>MIC Fluoroquinolone Meropenem P. aeruginosa Peak:MIC Selection PCN Aminoglycoside BS PCN 1-2 Cephalosporin 3-4 Cephalosporin Carbapenem 25 Enterobacteriaceae 2 1 Tobramycin 4 21 Ciprofloxacin 1 3.6

Exposure & Colonization Disruption of intestinal flora Inadequate host immune response Spore transmission McFarland, LV. J Med Microbiol 2005;54:101-111. CDI

Days of Antibiotic Therapy vs. Adjusted CDI Hazard Ratio <4 days Reference Stevens V et al. CID 2011;53(1):42-48. 1.4 4-7 days 95% CI 0.8, 2.4 3.0 8-18 days 95% CI 1.9, 5.0 7.8 >18 days 95% CI 4.6, 13.4 1 drug Reference 2.5 2 drugs 95% CI 1.6, 4.0 3.3 3-4 drugs 95% CI 2.2, 5.2 9.6 5 drugs 95% CI 6.1, 15.1 Number of Antibiotics vs. Adjusted CDI Hazard Ratio

Antibiotic CDI Adjusted Hazard Ratio (95% CI) Fluoroquinolones 4.0 (2.7, 5.9) Aminoglycosides 0.9 (0.3, 3.0) Clindamycin 1.9 (0.8, 4.4) 3 rd /4 th Generation Cephalosporins 3.1 (1.9, 5.2) Stevens V et al. CID 2011;53(1):42-48.