Introduction to Antimicrobial Resistance and Antibiotic Stewardship Mandelin Cooper, PharmD Clinical Pharmacist in Infectious Diseases Wesley Medical Center July 12, 2012

Objectives Explain the importance of antibiotic resistance Review strategies to prevent and reduce bacterial resistance Describe antibiotic stewardship programs and strategies Describe the stewardship programs in Wichita

Resistance is Increasing www.CDC.gov

Resistance is Increasing http://www.cddep.org/ResistanceMap/use

Antibiotic Development is Decreasing www.CDC.gov CID 2009; 48: 1-12.

Impact of Resistance Infections with resistant organisms: More likely to be hospitalized Longer length of stay Higher rates of death Estimated cost of treating infections with resistance in the USA is several billion dollars

Resistance & Prescribing Practices ↑ Resistant Organisms ↑ Mortality ↑ Morbidity ↑ Cost ↑ Awareness of MDR Organisms ↑ Use of Broad spectrum Antibiotics Overprescribing AAC 2008;Mar;52(3):813-21.

Emergence of Resistance Two Primary Components Endogenous expression of resistance that occurs because of selective pressure (i.e. antibiotic use) Person-to-person spread Good Infection Control Practices are Essential!

Basic Types of Resistance Intrinsic resistance Lack of drug binding site Drug unable to penetrate Acquired resistance Mutations Plasmids Exchange of DNA

Selection Pressure Squeezing the Balloon Extensive use of single drug classes leads to an increased amount of resistance Heterogeneity through individualization of drug selection may stabilize the selection of resistance JAMA 1998; 208 (14): 1270-1.

Selection for antimicrobial-resistant Strains Dominant Antimicrobial Exposure x Resistant Strains Rare x Once resistant strains of bacteria are present in a population, exposure to antimicrobial drugs favors their survival. Reducing antimicrobial selection pressure is one key to preventing antimicrobial resistance and preserving the utility of available drugs for as long as possible. www.cdc.gov Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Accessed 6/17/2010

Collateral Damage Use of broadspectrum antibiotics can cause unintended resistance to develop in pathogens that are not being targeted for treatment JAMA 1998; 208 (14): 1270-1.

Collateral Damage C. difficile Use of almost every antibiotic has been reported to cause C. difficile Broader spectrum and prolonged use of antibiotics increases the risk of development However, it has been known to occur with only ONE dose Decreasing usage of fluoroquinolones & cephalosporins have been associated with decreased incidence of C. difficile Infect Control Hosp Epidemiol 2010; 31(5) JAC Advanced Access June 2011 doi:10.1093/jac/dkr253. CID 2011; 53(1): 42-8.

Collateral Damage Vancomycin Resistant Enterococcus (VRE) Fluoroquinolones and Cephalosporins Methicillin Resistant Staph Aureus (MRSA) Patients exposed to antibiotics are 2 times as likely to acquire MRSA as patients who are not exposed Patients exposed to quinolones are 3 times as likely to acquire MRSA AAC 2002;46(6):1619-28. Ann Intern Med 2001;135:175-83. J Antimicro Chemo 2008; 61:26-38

Collateral Damage Carbapenem-Resistant Enterobacteriaceae (CRE or KPC) Carbapenems, cephalosporins, fluoroquinolones, and vancomycin Antimicrobial stewardship would be most effective if efforts are directed toward an overall decrease in antimicrobial use rather than targeting a specific antimicrobial class CID 2011; 53(1): 60-7.

Other Examples Fluoroquinolones select for resistance to carbapenems in Pseudomonas aeruginosa Fluoroquinolones may have caused the Hyper-producing toxin strains of C. difficile Clindamycin usage is a known cause of C. difficile Ceftazidime increases the amount of ESBLs CID 2007; 45:S112-21. CID 2005; 41:1254-60. CID 2008; 46:S19-31

Kansas And Antibiotic Usage Number of Rx per 1000 population = Higher than the National Average http://www.cddep.org/ResistanceMap/use

Did You Know? According to the literature: Up to 50% of antimicrobial use is inappropriate CID 2007;44:159-77.

Inappropriate and unnecessary antimicrobial use leads to increased resistance CID 2007;44: 159-77

Antibiotics and Emergence of Resistance Changes in antimicrobial use are paralleled by changes in resistance Patients with resistant organisms are more likely to have received prior antimicrobials Areas with the highest amount of resistance have the highest amount of antibiotic use Increased duration of antibiotics increases the risk of colonization with resistant organisms CID 2007;44: 159-77

Use Antibiotics Appropriately Goal: Use antibiotics to effectively treat a patient and minimize the development of resistance

Use Antibiotics Appropriately Minimize the risk of infection Hand hygiene Remove unnecessary lines and catheters etc. Only treat a patient if they have an infection Do NOT treat contamination Do NOT treat colonization Do NOT treat asymptomatic bacteriuria

Use Antibiotics Appropriately Initial therapy MUST be appropriate Use antibiogram data Know the difference between community and nosocomial infections Use Evidence Based Guidelines Meningitis, Pneumonia, Endocarditis, Vancomycin, C difficile, MRSA etc. Use Appropriate Doses of Antibiotics Ex. Vancomycin troughs <10 → increased resistance CID 2011; 52: 1-38.

Antibiogram A cumulative summary of bacteria species susceptibility to antibiotics in a specific hospital within a defined period of time Each hospital will have their own antibiogram Intranet at each respective institution Pocket cards are available Updated annually

(percent susceptible) Antibiogram Fantastic University Hospital GRAM-NEGATIVE AEROBES (percent susceptible) Total Isolates Ampicillin Ampicillin/Sulbactam Piperacillin/ Tazobactam Cefazolin Cefotetan Ceftriaxone Ceftazidime Cefepime Meropenem Ciprofloxacin Gentamicin Sulfamethoxazole Trimethoprim/ MIC breakpoint (mg/L) <8 <16 <4 <1 <2/38 Enterobacter cloacae 30 70 63 97 100 Escherichia coli 184 55 66 95 89 99 94 75 76 Divided into Sections* Most common and clinically relevant isolates are included Percentage is the # of isolates susceptible to the antibiotic Percentage includes every isolate tested Gray areas are not tested or not susceptible This is an example of the antibiogram The bacteria is listed in the left hand column And the antibiotics are listed along the top with the respective susceptibility breakpoint Percentages given for each antibiotic are the % susceptible % includes every isolate tested regardless of location or type of infxn Gray areas are not normally tested or not susceptible

Limitations of Antibiograms Not reflective of each individual unit but describes the hospital overall Some patient areas will have less resistance and some will have more Antibiogram specific for the ICUs Not reflective of specific types of infection but all cases where the bacteria was isolated Limitations of antibiograms are that They are Not reflective of each individual unit but describes the hospital overall Some patient areas will have less resistance and some will have more Some institutions have Antibiograms specific for the ICUs or other areas of the hospital The antibiogram is also Not reflective of specific types of infection but all cases where the bacteria was isolated

Use Antibiotics Appropriately Obtain appropriate specimens to aid in diagnosis and treatment of infections De-escalate antibiotics as early as possible Maximize the efficacy and minimize the toxicity of the agent used Minimize the duration of antibiotics Ex. do not use prolonged antibiotics post-operatively (<24 hours for most surgeries)

Duration of Therapy Prevent the Emergence of Resistance Decrease Selective Pressure Short Course Antibiotic

Duration of Therapy Post-op Prophylaxis: CAP: 5 days < 24 hours needed for most surgeries CAP: 5 days 5 RCTs show that 5 days is as effective as longer courses VAP: 7 days per guidelines 8 vs 15 days showed similar outcomes Intra-abdominal: 4-7 days after source control CID 2011; 52(10): 1232-40. CID 2007; 44: S27-72. Am J Respir Crit Care Med 2005; 171:388-416. JAMA 2003; 290: 2588-98.

Duration of Therapy Pyelonephritis Guidelines 14 days Meta-analysis of short course (7-14 days) vs long course (14-21 days) showed no significant differences CID 2011; 52(10): 1232-40. CID 2011; 52: e103-20. CID 2010; 50: 133-64.

What is Antibiotic Stewardship? The optimal selection, dose, and duration of an antimicrobial that results in the best clinical outcome for the treatment of an infection, with minimal toxicity to the patient and minimal impact on subsequent development of resistance Diag Microbial Infect Dis 2007; 57 (suppl 3) S77-83.

Stewardship Stewardship NOT ONLY limits inappropriate antibiotic usage Optimizes antibiotic selection Dosing Route Duration of Therapy CID 2007;44:159-77

The Stewardship Team Infectious Diseases Physician Clinical Pharmacist with Infectious Disease training Microbiology Infection Control Hospital Epidemiologist Information System Specialist CID 2007; 44 (159-77)

Stewardship Methods Education Guidelines and Clinical Pathways Antimicrobial Order Forms (i.e. Pre-printed order sets) Dose optimization Parenteral to Oral Conversion Streamlining or de-escalation of therapy CID 2007;44:159-77.

Wichita Antibiotic Stewardship Programs Both Programs Dr. Creswell is the medical director Full time pharmacist who follows patients concurrently and makes written/oral recommendations IV to PO

Wichita Antibiotic Stewardship Programs Both Programs Formulary restriction (multiple therapeutic interchanges) Work closely with Microbiology and Infection Control Develop and maintain order sets and clinical pathways

Wichita Stewardship Programs Wesley: Mandelin Cooper, PharmD Clinical Pharmacists in every unit Adult Renal Dosing Program Kinetic service Via Christi: Jennifer Schmitz, PharmD Clinical Pharmacists throughout the hospital Adult renal dosing in place for multiple medications Kinetic service coming soon

Goals of Our Stewardship Programs Improve patient outcomes Optimize antibiotic therapy for patients Minimize the development of resistance on a patient, hospital and citywide basis

Goals of Our Stewardship Programs Reserve agents that treat MDR organisms for cases of resistance Educate on appropriate use of antibiotics Reduce antibiotic expenditures Meet CMS Core Measures

Daily Stewardship Functions List of patients on antibiotics Review by clinical pharmacist Potential changes identified Chart reviewed Consultation with ID physician Additional micro information obtained Prescribing physician contacted

Does Stewardship Work? Improves Patient Outcomes Decreases Resistance Optimizing empiric antibiotic selection Optimizing dosing of antibiotics Decreases Resistance Improve or maintain antibiotic susceptibilities Decreases cost for patients and hospitals

Wesley Results - 2011 Because of - Appropriate Gentamicin usage we have reduced P. aeruginosa resistance Because of - Appropriate Ceftazidime usage we have reduced P. aeruginosa resistance Because of - Appropriate Fluoroquinolone usage we have retained P. aeruginosa susceptibilities Many institutions have lost the ability to use the older, less toxic drugs due to less than optimal use

Wesley Results 2010 & 2011

Patient Stewardship Case AB is a 69 yr old F from a nursing home admitted to MICU for possible HCAP and is started on Cefepime/Tobramycin/Vancomycin empirically PMH: DM, HTN, COPD, Pseudomonas pneumonia 2 years ago Scr 1.0, CrCl = 65 ml/min

Patient Stewardship Case Day #1: RPh would review the patient for drug selection and dosing Patient has a history of Pseudomonas so duplicate coverage empirically is recommended Past Pseudomonal culture results are compared to the antibiotics prescribed Cefepime: Dosing would be automatically adjusted at order entry Vancomycin/Tobramycin: Prescriber would be contacted if changes were necessary or if RPh consulted to dose they would be dosed for pneumonia

Patient Stewardship Case Day #2: Sputum gram stain shows GNR and has early growth of gram negative rods RPh would review culture and recc to d/c the vancomycin

Patient Stewardship Case Day #3: Sputum Culture grows pan sensitive Pseudomonas and is finalized RPh would recc to d/c the vancomycin (if not already done) and the tobramycin Once sensitivities are known duplicate coverage for pseudomonas is unnecessary One agent improves patient outcomes by decreasing the risk of toxicity AAC 1997; 41 (5): 1127-33. AAC 2003; 47 (9): 2756-64. Pharmacotherapy 2011; 31 (6): 598-608.

Patient Stewardship Case Day #8: AB is on Cefepime D#8 for pseudomonas pneumonia CXR improved Patient is clinically stable RPh would discuss with MD length of therapy and recc to d/c or place stop dates

Take Home Message Antibiotic resistance is a problem and we have limited antibiotics in the pipeline Stewardship is a group effort between multiple disciplines Only give patients antibiotics if they have an infection De-escalate antibiotics as early as possible Treat for the appropriate length of time

Introduction to Antimicrobial Resistance and Antibiotic Stewardship Mandelin Cooper, PharmD Clinical Pharmacist in Infectious Diseases Wesley Medical Center July 12, 2012