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

2. 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

3. Resistance is Increasing

4. Resistance is Increasing

5. Antibiotic Development is Decreasing
CID 2009; 48: 1-12.

6. 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

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

8. 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!

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

10. 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):

11. 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.
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Accessed 6/17/2010

12. 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):

13. 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: /jac/dkr253.
CID 2011; 53(1): 42-8.

14. 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):
Ann Intern Med 2001;135:
J Antimicro Chemo 2008; 61:26-38

15. 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.

16. 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:S
CID 2005; 41:
CID 2008; 46:S19-31

18. Kansas And Antibiotic Usage
Number of Rx per 1000 population
= Higher than the National Average

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

20. Inappropriate and unnecessary antimicrobial use leads to increased resistance
CID 2007;44:

21. 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:

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

23. 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

24. 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.

25. 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

26. (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

27. 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

28. 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)

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

30. 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):
CID 2007; 44: S27-72.
Am J Respir Crit Care Med 2005; 171:
JAMA 2003; 290:

31. 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):
CID 2011; 52: e
CID 2010; 50:

32. 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.

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

34. 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)

35. 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:

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. Wesley Results
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

44. Wesley Results 2010 & 2011

45. 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

46. 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

47. 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

48. 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):
AAC 2003; 47 (9):
Pharmacotherapy 2011; 31 (6):

49. 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

50. 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

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