Antimicrobial Resistance: Selective Pressure Mulvey M R, Simor A E CMAJ 2009;180:408-415
Antimicrobial Resistance: Mechanisms of genetic resistance to antimicrobial agents Coates A et al. Nature Reviews Drug Discovery 1, 895-910 (November 2002)
Antimicrobial Resistance: Mutation & Selection/Acquired Resistance Enzyme Inactivation -lactamase production ESBL production Carbapenemase New Delhi Metallo- -lactamase Examples: E. coli producing -lactamase or ESBL Klebsiella producing carbapenemase
Antimicrobial Resistance: Mutation & Selection/Acquired Resistance Alteration of the target site Altered protein binding Altered DNA enzymes Examples: MRSA – methicillin-resistant Staph. aureus PBP (Penicillin binding protein)-resistant Strep. pneumo Ciprofloxacin resistance in Mycobacterium
Antimicrobial Resistance: Mutation & Selection/Acquired Resistance Decreased access to the target site Efflux pumps - Antimicrobial is pumped out of the bacteria before it accumulates Altered structure of outer membrane proteins or porins Example: Tetracycline TetK efflux in Staph. aureus Imipenem-resistant Pseudomonas
Examples of Common Resistant Bugs CMAJ February 17, 2009 vol. 180 no. 4 408-415
Multi-Drug Resistant Organisms (MDROs) Prevalent in hospitals & long-term care facilities Not as likely to cause disease in LTCF (colonization) Cause the same infections as non-MDROs BUT Fewer antibiotic choices Isolation Increased length of stay Increased risk of ADE Increased mortality = Increased $$$
MDRO Treatment Options: Community-acquired MRSA (Ca-MRSA) Transmission Contaminated hands Skin-to-skin contact Crowded conditions Poor hygiene Increased risk Athletes, military recruits, children, Pacific Islanders, indigenous populations, men who have sex with men, animal owners, ED patients, cystic fibrosis patients, urban underserved communities, and prisoners Clinical Microbiology Reviews, July 2010, p. 616-687, Vol. 23, No. 3
Mild-moderate infection Doxycycline or Minocycline Caution with susceptibility tests Clindamycin Trimethoprim/Sulfamethoxazole Severe infection Vancomycin - PREFERRED Daptomycin (NOT for pneumonia) Linezolid (pneumonia) Dalfopristin/Quinupristin Limited by ADE arthralgias Tigecycline (cSSTI, intra-ab) Low serum concentrations Telavancin (cSSTI) Ceftaroline (cSSTI) **Use varies greatly by site of infection, refer to IDSA MRSA Guidelines 2011** *Adjuncts: rifampin (also in combo with FQs), gentamicin, beta-lactams Clinical Microbiology Reviews, July 2010, p. 616-687, Vol. 23, No. 3 Clin Infect Dis. (2011) 52 (suppl 5): S397-S428. doi: 10.1093/cid/cir153 Gilbert DN, et al. Sanford Guide to Antimicrobial Therapy 2011, 41st ed. MDRO Treatment Options: Community-acquired MRSA (Ca-MRSA)
MDRO Treatment Options: Penicillin-Resistant Strep. Pneumoniae (PRSP) Causes respiratory tract infections and meningitis Resistant to: Penicillin G *due to alteration in penicillin-binding proteins (PBPs) Variable resistance to cephalosporins, macrolides, tetracyclines, clindamycin Alternatives: Amoxicillin/clavulanate Ceftriaxone, cefotaxime Respiratory quinolones Linezolid Vancomycin +/- Rifampin Am J Respir Crit Care Med ; 2005 ; 171 : 388 -416Gilbert DN, et al. Sanford Guide to Antimicrobial Therapy 2011, 41st ed.
MDRO Treatment Options: Vancomycin-resistant Enterococci (VRE) Usually Enterococcus faecium Resistant to: Vancomycin, Aminoglycosides, Penicillins, Quinolones Treatment options: Linezolid Quinupristin/dalfopristin Faecium only Combination therapy recommended Tigecycline Daptomycin Site Specific– Urinary Tract Infections Nitrofurantoin Fosfomycin CMI 16:555,2010Gilbert DN, et al. Sanford Guide to Antimicrobial Therapy 2011, 41st ed. Clin Infect Dis. (2010) 51 (1): 79-84http://emedicine.medscape.com/article/216993-treatment
MDRO Treatment Options: Pseudomonas aeruginosa Resistant to: Meropenem, Imipenem Alternatives: Possible evidence for extended-infusion carbapenems Fluoroquinolones – cipro > levo Anti-pseudomonal aminoglycosides (APAG) Anti-pseudomonal penicillins +/- APAG Ceftazidime, Cefepime +/- APAG Aztreonam Combos of Doripenem + Polymyxin B +/- Rifampin Fosfomycin + APAG Polymyxin B Colistin Lister PD, Wolter DJ Clin Infect Dis 2005;40:S105-114 Livermore DM. Clin Infect Dis 2002;34:634-40 Am J Respir Crit Care Med ; 2005 ; 171 : 388 -416 Gilbert DN, et al. Sanford Guide to Antimicrobial Therapy 2011, 41 st ed. Antimicrob Agents Chemother. 2008 October; 52(10): 3795–3800
MDRO Treatment Options: Extended Spectrum Beta Lactamase (ESBL)- Producing Organisms Risk Factors for ESBLs in non-hospitalized patients Recent antibiotic use Residence in long-term care facility Recent hospitalization Age >65 years Male 34% of ESBL-producing isolates from patients with no recent health care contact Ben-Ami R et al. Clin Infect Dis 2009;49:682-90
MDRO Treatment Options: ESBL-producing Organisms Most commonly Klebsiella or E.coli Resistant to: 2 nd /3 rd generation Cephalosporins Aztreonam Aminoglycosides Fluoroquinolones Alternatives: Carbapenems (some emerging resistance) Ertapenem for E. coli In-vitro: Cefepime, Piperacillin/tazobactam, Tigecycline Colistin Fosfomycin Am J Respir Crit Care Med ; 2005 ; 171 : 388 -416Gilbert DN, et al. Sanford Guide to Antimicrobial Therapy 2011, 41st ed.
MDRO Treatment Options: Carbapenemase and New Delhi Metallo KPC = CRE Most commonly Klebsiella or E.coli NDM-1 found in water samples in India Resistant to: All Carbapenems Aminoglycosides Fluoroquinolones Alternatives: Tigecycline Colistin
MDRO Treatment Options: Acinetobacter Up and coming “superbug” Found in soil and water Can live on skin & surfaces for days Predominately a colonizing organism
Therapy: ID Consult! Agents: Carbapenems (building resistance as of 2005) Susceptibility 32% to >90% Ampicillin/sulbactam +/- Meropenem Tigecycline - in combination only (e.g. + Amikacin) Polymyxin B + Imipenem/cilastatin + Rifampin Colistin Susceptibility 55% to >80% Other treatment therapies and combinations but Acinetobacter infections very MDRO: Mortality 20-50% MDRO Treatment Options: Acinetobacter Landman D et al. Arch Intern Med 2002;162:1515-20Kopterides P et al. Int J Antimicrob Agents 2007;30:409-14 Clin Infect Dis. (2010) 51 (1): 79-84Am J Respir Crit Care Med ; 2005 ; 171 : 388 -416 Gilbert DN, et al. Sanford Guide to Antimicrobial Therapy 2011, 41st ed.
IDSA Definition Antimicrobial Stewardship is an activity that promotes: – The appropriate selection of antimicrobials. – The appropriate dosing of antimicrobials. – The appropriate route and duration of antimicrobial therapy. What is an Antimicrobial Stewardship Program (ASP) Dellit TH, Owens RC, McGowan JE Jr et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for 1. developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007; 44:159-77
Antimicrobial Stewardship – Why? Boucher et al. Clin Inf Dis 2009 Not much in the pipeline
World Health Organization (WHO) 10 x ’20 Initiative Published in early 2010 by IDSA WHO identified antimicrobial resistance as a major issue Clin Infect Dis. (2011) 52 (suppl 5): S397-S428. doi: 10.1093/cid/cir153 Clin Infect Dis 2010;50:1081-83.
Antimicrobial Stewardship Programs (ASP) Plethora of literature on resistance and ASP Refer to local Antibiograms for most accurate resistant patterns leadstewardship.org and ASHP Educational Webinars under Infectious Diseases subsection Existing Webinars Summarize IDSA Guidelines (2007) http://cid.oxfordjournals.org/content/44/2/159.full ASP-supportive literature Success stories Personal & in literature Our focus: Key points, focused approach, resources
Purpose Optimize clinical outcomes Minimize unintended consequences of antimicrobial use Toxicity Selection of pathogenic organisms (e.g. C. diff) Emergence of resistance 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77.
ASP Guidelines Core Strategies Core Strategies Prospective audit with intervention and feedback Looking at antibiotic orders as they come, adjusting per pre-set guidelines Formulary restriction with pre-authorization UKMC: negative impact (let first dose go thru, intervene after) Supplemental Strategies Education, Education, Education Guidelines and clinical pathways Antimicrobial order forms (CPOE systems) Combination therapy De-escalation Dose optimization IV to PO conversion Antimicrobial cycling (least evidence, most controversial) 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77. ASHP Midyear 2010 CE Presentation – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution http://www.ashpmedia.org/symposia/4cpe/stewardship/
CDC: Methods to Improve Antimicrobial Use Passive prescriber education Standardized order forms Formulary restrictions Pre-authorization Pharmacy substitution Multidisciplinary DUE Performance feedback CPOE CDC: http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf
Guiding Tenets of ABX Use 1. Severe infection – start broad Get it wrong = in trouble 2. Get it IN the patient quickly (actual administration) First dose = most important 3. De-escalation of therapy is a necessity Right drug = narrowest-spectrum with successful response, causing the least collateral damage 4. Treat only as long as appropriate ASHP Midyear 2010 – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution: http://www.ashpmedia.org/symposia/4cpe/stewardship/
ASP Team Members Multidisciplinary problem that cannot be solved by one person Core members (eventual compensation is ideal) ID MD ID Pharmacist Adjunct members Microbiologist IT/Data Specialist Infection Control Professional and/or Epidemiologist 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77.
Roles of the Team Members Physician Champion Knowledgeable in Infectious Diseases Willing to teach untrained Pharmacist Willing to help promote cause Willing to work together Respected by peers Able to form working relationship with hospital administrator and pharmacy director *sometimes the largest hurdle to overcome 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77.
Roles of the Team Members Clinical Pharmacist ID-trained or strong willingness to learn backed by a solid foundation in antibiotics Helps establish program structure and protocol Aids in creating and/or overseeing Antibiograms Performs daily interventions Continually educates medical and pharmacy staff Raises pharmacy awareness and rallies support 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77.
Roles of the Team Members Microbiologist Provides surveillance data for Antibiogram Develops combination antibiotic Antibiograms Reviews current diagnostic tests and investigates pros and cons of incorporating new, novel tests 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77.
Roles of the Team Members Infection Control and/or Epidemiologist Implement/improve infection control measures Collect data regarding adherence and outcomes Monitor healthcare-acquired infection rates Investigate local outbreaks Share daily reports with pharmacist Isolation due to MDROs 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77.
Roles of the Team Members IT/Data Manager Establish method for obtaining data Develop/adapt database to record interventions Prepare annual reports for administrative arm Aid in statistical analysis of program *most programs lack this member and the pharmacist picks up the slack 2007 IDSA ASP Guidelines: Dellit TH. Clin Infect Dis 2007;44:159-77.
Performance Measures Essential in showing value of Stewardship program Examples: Antibiogram Performed at least annually Medication Use Evaluations (MUE) Utilization/Purchasing Data quarterly MDRO rates Blood contamination Rates Quality Measures
Can this be done at smaller hospitals? 120 bed hospital in Monroe, LA ID MD, clinical PharmD, infection control, microbiologist *paid MD and PharmD Concurrent chart review 3 days/week (limited resources) Study period = 1 year (all the way back in 2000) Targeted patients Multiple, prolonged, or high-cost antibiotics Initial pushback from medical staff 69% recommendation acceptance 19% reduction in antibiotic expenditures (saved $177,000!) LaRocco et al. CID 2003.
Tier System Approach Different approaches for different budgets/personnel Low-lying fruit Start small, simple, and smart Identify “Problem Child” units or antibiotics Easy “wins” Build ASP credibility IV to PO Conversions; De-escalation of therapy; Pre-printed order sets Raising awareness costs = $0 Improve the systems you already have in place
CDC’s 4 Principles: 1. Infection prevention Catheters, VAP 2. Accurate and prompt diagnosis and treatment Etiology of infectious process 3. Prudent use of antimicrobials 4. Prevention of transmission Hand washing, isolation, etc. CDC: http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf A Few Examples: Management of MDRO in Healthcare Settings
A Few Examples: Restriction vs. Facilitation Consider Facilitation vs. Restriction The goal of an ASP is NOT to limit appropriate use of antibiotics More restricted antibiotics = sicker patient usually is More delay More pushback from medical staff Mixed signal of ASP The only dose proven to save lives in the first one! Allow according to restriction protocol, then adjust prn ASHP Midyear 2010 – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution: http://www.ashpmedia.org/symposia/4cpe/stewardship/
Many Available Resources ASHP – ashp.org IDSA – idsociety.org CDC – cdc.gov CID – cid.oxfordjournals.org Available for purchase Sanford Guide to Antimicrobial Therapy Johns Hopkins ABX Guide hopkins-abxguide.org
ASP: Why now? 1. Antimicrobial overuse/misuse affects resistance 2. Antimicrobial resistance is at unprecedented levels 3. Typically financially self-supporting Although this should be a secondary goal 4. It’s the RIGHT THING TO DO ASHP Midyear 2010 – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution: http://www.ashpmedia.org/symposia/4cpe/stewardship/
What is the status of ASP in your institution? Question posed by speaker at ASHP Midyear Meeting 2010 10% No ASP, no plans to pursue one 20% No ASP, need to establish one 30% Currently discussing need for an ASP 20% The ASP we have is not very effective 20% The ASP we have is highly regarded So if you don’t have an ASP, you’re not alone but you may be soon ASHP Midyear 2010 – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution: http://www.ashpmedia.org/symposia/4cpe/stewardship/
Barriers to Establishing ASPs 1. Lack of funding ASPs often function in personnel’s spare time initially 2. Shortage of adequately-trained ID MDs and Pharmacists 3. Lack of pharmacy leadership support 4. MD autonomy 5. Competition for funding Money is going to go to programs that are mandated 6. Antagonistic colleagues ASHP Midyear 2010 – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution: http://www.ashpmedia.org/symposia/4cpe/stewardship/ Owens RC, Shorr AF, Deschambeault AL. Antimicrobial stewardship: shepherding precious resources. Am J Health-Syst Pharm. 2009; 66(Supp 4):S15-22
Building your Case 1. Current situation is likely costing institution unnecessary dollars 2. Clinical issues make timely program implementation compelling 3. A formal business plan is essential 4. Need to demonstrate return on investment (ROI) over a reasonable time period ASHP Midyear 2010 – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution: http://www.ashpmedia.org/symposia/4cpe/stewardship/
Conclusion: Baby Steps Avoid making cost-reduction your #1 goal Educate personnel on ASP Basics Identify glaring problem areas and establish areas of improvement Work on multidisciplinary development of evidence-based guidelines Based on national guidelines, tailored to institution based on resistance patterns Work to ensure de-escalation and antibiotic stop dates Improve efficiency of pharmacy distribution system Facilitation vs. Restriction ASHP Midyear 2010 – Antimicrobial Stewardship: Building the Case and Overcoming Barriers in your Institution: http://www.ashpmedia.org/symposia/4cpe/stewardship/
Conclusion: Needs identified by IDSA in 2011 publication National Funding Legislative action Research and Development ASPs Novel Antibiotics Resistance, especially as it relates to MDROs Clin Infect Dis. (2011) 52 (suppl 5): S397-S428. doi: 10.1093/cid/cir153
ASP Resources Online Webinars http://www.ashp.org/menu/Education/OnlinePrograms.aspx http://leadstewardship.org/activities.php ASP-specific Websites Nebraska Medical Center www.nebraskamed.com/asp Univ. of Kentucky www.hosp.uky.edu/pharmacy/AMT/default.html Univ. of Pennsylvania www.uphs.upenn.edu/bugdrug Goff, DA. ASHP Advantage Newsletter. CE in the Mornings. Working Together: Implementing Interdisciplinary Antimicrobial Stewardship Programs. March 2010.