1. Kenneth Lawrence, PharmD
The Role of Antimicrobial Stewardship in the Prevention of Clostridium Difficile Infections
Kenneth Lawrence, PharmD
Lisa Davidson, MD
Tufts Medical Center
Department of Pharmacy
Division of Geographic Medicine and Infectious Disease

2. Disclosures
LD: No financial disclosures
KL: No financial disclosures

3. The microbiome….
Microbes account for 60% of the earth’s biomass
Microbes are ancient and have been in existence for 350 million years
There are 5-10 times more bacteria living on or in a human than human cells

4. Repeated antibiotics alter beneficial gut germs

5. Colonizers vs Pathogens
The majority of bacteria that live in and on humans are colonizers, living in a delicate balance with their human host that has evolved of millions of years.
Pathogens are microbes that depend upon a pathogenic relationship with their hosts for survival.
By using invasive properties, such as toxins and virulence factors, these pathogenic bacteria establish a niche that is devoid of competition from other nonpathogenic microbes.
Falkow, 2005; IOM 2006

6. Clostridium difficile
Anaerobic spore-forming bacillus
Transmission of spores in vegetative state
Fecal-oral transmission
In 1978, C difficile was identified as the major cause of Antibiotic-associated diarrhea
Multiple studies have demonstrated the association of CDI and antimicrobials
96% of patients with CDI received antimicrobials within the 14 days
Prior to 2000: The majority of CDI were nosocomial
Presentation ranged from symptomless carriage, to mild or moderate diarrhea, to fulminant and sometimes fatal pseudomembranous colitis
L Mcdonald. Emerg Infect Dis Mar;12(3): ;
MM Olson et al. Infect Control Hosp Epidemiol 1994;15:371–381.

7. CDI Mortality Rates per million Population, US, 1999–2004
Redelings MD, et al. Emerg Infect Dis 2007;13:

8. Clostridium difficile: a new strain emerges
Rates of nosocomial C. difficile-associated diarrhea (CDAD) in the US doubled from 31 to 61 per 100,000 between 1996 and 2003.
From 2003 to 2006, C. difficile infections were observed to be more frequent, severe and refractory to standard therapy, and more likely to relapse.
Pittsburgh, 2000:: Life-threatening disease increased from 1.6% to 3.2%
: 26 colectomies and 18 deaths
Quebec, 2004
30-day attributable mortality 6.9%
12-month attributable mortality 16.7%
Muto C, et al. Infect Control Hosp Epid. 2005
Pepin J, et al. CMAJ. 2005

9. Clostridium difficile: a new strain emerges
Strain NAP1/BI/027
Virulence related to increased toxin production compared to conventional strains
-deletion mutations in the tcdC inhibitory gene
Production of a binary toxin
Fluoroquinolone use strongly correlated with the emergence of this strain
Warny M, et al. Lancet. 2005;366:
S Dial et al AMA Dec 21;294(23):

10. Antibiotics and CDI Antibiotics increase risk of CDI
1. disrupt normal colonic flora
2. selecting for resistant C difficile strains
Clindamycin: 1970 and 1908’s
Initial drug associated with CDI
published reports documenting control of outbreaks due to highly clindamycin resistant strains with restricted clindamycin use
2nd and 3rd generation Cephalosporins: 1990’s
Widespread use starting in the 1990s
Associated with increased rates of CDI as compared with β-lactams (pip-tazo)
Antimicrob Chemother Nov;40(5): ; Aliment Pharmacol Ther Dec;12(12): J Hosp Infect Jun;54(2):104-8.; Infect Control Hosp Epidemiol Feb;15(2):88-94.

11. CDI and Fluoroquinolones
Epidemic in Quebec 2004: Matched logistic-regression analysis (case vs controls) demonstrated increased rates of CDI with:
exposure to 3rd gen cephalosporins (OR 3.8)
exposure to fluoroquinolones (OR 3.9)
Subsequent studies have demonstrated significant increases in CDI associated with fluoroquinolones
Texas: increase in fluoroquinolone use preceded the beginning of outbreak by 9 months (P<0.001)
Atlanta, Long term care facility
- significant associations between CDAD and use of clindamycin and gatifloxacin
-increased risk of CDAD with increasing duration of gatifloxacin therapy
N Engl J Med 2005; 353: ; Muto et al Infect Control Hosp Epidemiol 2005;26:273–280; Clinical Infectious Diseases 2004;38:640–64

12. Is there a solution?
“Finally, an important method of controlling past outbreaks of C. difficile–associated disease has been restriction of the use of antimicrobial agents implicated as risk factors for the disease…. … Because fluoroquinolones have become a mainstay in the treatment of several common infections, a large-scale restriction of the use of these drugs would be quite difficult…..it will be important either to reconsider the use of fluoroquinolones or to develop other innovative measures for controlling C. difficile–associated disease.”
L Mcdonald, et al. N Engl J Med 2005; 353:

13. Antimicrobial Stewardship and Cephalopsorin Use
Design:
Prospective evaluation of antimicrobial management program implemented
Goal: to minimize inappropriate use of 3rd-generation cephalosporins, broadened to audit use of other antimicrobials
Time period: 7 years
3 interventions: choice, shorter duration, switch from IV to PO
Assessed incidence of C. difficile, resistant Enterobacteriaceae, VRE, and MRSA in NNIS system hospitals of comparable size
Reduction in CDAD (p=0.002)
NNIS = National Nosocomial Infections Surveillance system
Carling P, et al. Infect Control Hosp Epidemiol. 2003;24:

14. Successful use of feedback to improve antibiotic prescribing and reduce CDI
Implemented cephalosporin restrictive antibiotic policy with audit and feedback of antibiotic use and CDI rates
Significant reduction in use of cephalosporins and amox/clav (P=0.03)
Significant reduction in rate of CDI (P = )
Fowler S et al.
J. Antimicrob. Chemother.
2007;59:

15. Reduction in the use of antibiotics on the course of an epidemic of CDAD caused by the hypervirulent NAP1/027
In setting of epidemic of CDAD, new infection control procedures incidence not associated with decreased incidence (P=.63)
Development of a nonrestrictive antimicrobial stewardship program (education, telephone feedback, guidebook).
Between to , total and targeted antibiotic consumption decreased by 23% and 54%, and the incidence of CDAD decreased by 60%.
Implementation of the antimicrobial stewardship program was followed by a marked reduction in CDAD incidence (P=.007).
Vaiquette et al. Clin Infect Dis Sep 1;45 Suppl 2:S

16. Acquisition rates of C. difficile carriage (P = 0.84):
Impact of different empirical antibiotic treatment regimens for community-acquired pneumonia on the emergence of Clostridium difficile.
Acquisition rates in patients hospitalized for CAP in a low endemic region
Nosocomial acquisition rate of C. difficile carriage was 11.2%. No nosocomially acquired CDI occurred.
Acquisition rates of C. difficile carriage (P = 0.84):
11.9% (5/45) in moxifloxacin
11.1% (5/47) in beta-lactam
9.0% (1/14) in beta-lactam plus macrolide- or fluoroquinolone-treated patients
Risk factors for C. difficile carriage:
antibiotic treatment >7 days [odds ratio (OR) 3.89; 95% confidence interval (CI) 1.30 to 11.79]
hospitalization during the past 3 months (OR 4.08; 95% CI 1.40 to 11.90).
J Antimicrob Chemother Sep 7. [Epub ahead of print]

17. From Infect Control Hosp Epidemiol 31(10):1030-1037
From Infect Control Hosp Epidemiol  31(10): © 2010 by The Society for Healthcare Epidemiology of America. All rights reserved. For permission to reuse, contact
CDI cases were defined as any inpatient with a stool toxin assay positive for C. difficile. Recurrent cases were defined as any patient with repeated episodes of CDI within 8 weeks of each other and were excluded from our study. An HCF was defined as acute care, long‐term care, long‐term acute care, or other HCF in which skilled nursing care was provided and in which patients were admitted at least overnight.
Annual incidence rates of Clostridium difficile infection (CDI) for all 5 healthcare facilities (HCFs) combined, according to surveillance definition. Solid lines indicate a statistically significant increase in incidence during the study period ( , determined by use of the χ2 test for trend). The open symbols represent CDI cases per 10,000 patient‐days, and the solid symbols represent CDI cases per 1,000 admissions.

18. Antimicrobial Resistance is a National Quality and Safety Issue

19. Antimicrobial Therapy
Appropriate initial antibiotic while improving patient outcomes and heathcare
Unnecessary
antibiotics and adverse patient outcomes and increased cost
Anti-
Microbial
Stewardship
A Balancing Act

20. Bad Bugs: No ESKAPE
Enterococcus
S. aureus
Klebsiella spp.
Acinetobacter
P. aeruginosa
Enterobacter spp.
ESCAPE: Recent literature suggests we should be expanding this list to include “C” for C diff due to increased prevelance and lack of appropriate antimicrobials
Boucher H, et al, Clin Infect Dis 2009;48:1-12
Patterson, et al, Clin Infect Dis 2009;49:992-3 20

21. What is Antimicrobial Stewardship
Antimicrobial stewardship involves the optimal selection, dose and duration of an antibiotic resulting in the cure or prevention of infection with minimal unintended consequences to the patient including emergence of resistance, adverse drug events, and cost.
Ultimate goal is improved patient care and healthcare outcomes
Dellit TH, et al. CID 2007;44:159-77,
Hand K, et al. Hospital Pharmacist 2004;11:459-64
Paskovaty A, et al IJAA 2005;25:1-10

22. ASHP Statement on ASP 2009 Promoting optimal antimicrobial use
Reducing the transmission of infections

23. Building The Team Antimicrobial Control Infectious Diseases
Specialists
Administration
Infection Control
Antimicrobial
Control
Microbiology
Clinical Pharmacists
Pulmonary/
Intensivist
Infectious diseases specialists are one important resource for providing input, but many other professionals also contribute to optimal care for patients with infections.
Like all patient safety endeavors, multidisciplinary collaboration is key!
OR Personnel
Nursing
Surgical Infection
Experts/Surgeons

24. Antimicrobial Stewardship Strategies
Front end: Formulary restriction and preauthorization
Back end: Interventions after antimicrobials have been prescribed
BOTH: Prospective audit with intervention and feedback
Supplemental Strategies
Education, guidelines, clinical pathways
Dose optimization via PK-PD
De-escalation/Streamlining
Antimicrobial order forms/order sets if CPOE
IV-PO switch
Computerized decision support
Antimicrobial cycling
Combination therapy
Dellit TH, et al. CID 2007;44:159-77
Hand K, et al Hospital Pharmacist 2004;11:459-64
Paskovaty A, et al IJAA 2005;25:1-10

25. Antimicrobial Stewardship at Tufts Medical Center
Ensure appropriate empirical antimicrobial therapy
Optimize Antimicrobial choice, dosage, route, duration
Stabilize and improve antimicrobial resistance
Improve quality fo care Reduce cost
IV to PO
Duration of treatment
Formulary management
De-escalation therapy, stopping unneeded treatment
Education and infectious disease treatment pathways
Reduce medication errors due to antimicrobials
2 part time ID physicians, 1 full time ID PharmD
Prospective audit with intervention and feedback
Formulary restriction and preauthorization

26. “Front End” Restriction at the time the antimicrobial is prescribed:
Formulary vs non-formulary
Target specific antimicrobials associated with high rates of resistance or $$$
May target a specific disease or indication
In order to receive restricted antibiotics, a prescriber must discuss with stewardship team
performed by either an infectious diseases physician and/or a clinical pharmacist with infectious diseases training
Requires resources early in the intervention process

27. “Back end” Prescribers are allowed to order antibiotics upon admission
Antibiotic orders are reviewed at specified intervals after initiation
May be restricted to particular patient populations
Ex: Cefepime and Zosyn in ICU for up to 72 hours
Ex: Echinocandins in Febrile Neutropenia
May be restricted to formulary drugs or by using a clinic pathway or protocol
Ex: Pneumonia protocol

28. Survey of Antimicrobial Stewardship Practice
39% of respondents had an ASP
92% of institutions with an ASP had an ID consult service, compared to only 66% of institutions without an ASP.
ASP institutions measured effectiveness of their programs by antimicrobial expenditures (58%), antimicrobial resistance (52%) and frequency of physician acceptance (50%).
80% of all participating hospitals used antimicrobial order restriction as the most common technique
Median yearly antimicrobial expenditures for antibacterials and antifungals was $1.35 million for institutions with an ASP, versus $800,000 for institutions without an ASP
75% of participants from institutions with an ASP stated physicians at their institutions agreed with the antimicrobial restrictions, versus only 46.6% at institutions without an ASP
Nadarki et al. SHEA 2010

31. Educational Strategies
Point Prevalence Surveys
Newsletter
Posters
Guideline dissemination and guidebooks
Nursing in-services, Grand rounds and other conferences
AMT Champion
Question of the week
Infrequently successful alone!!!
Works well when used as a component in a ASP

32. More on the Back end: Getting your pharmacist really excited…
Automatic IV to PO conversion
Automatic Drug conversion
Ex: transfers from outside hospital – get on formulary drugs
Alternative dosing regimens
Continuous or prolonged infusions of ß-lactam
Increased frequency of dosing (e.g, meropenem)

33. Computer Surveillance
Sentri7
SafetySurveillor-Pharmacy
TheraDoc
CPOE
Benchmarking
Antimicrobial use

34. The government vs. the microbes Center for Medicare and Medicaid Services (CMS) Non Payment Conditions
Object inadvertently left in after surgery
Air embolism
Blood incompatibility
Catheter associated urinary tract infection
Pressure ulcer (decubitus ulcer)
Vascular catheter associated infection
SCIP/ Surgical site infection
Certain types of falls and trauma

35. Barriers to Implementing ASP
Lack of understanding the problem
Antimicrobial resistance is a Quality and Safety issue
Time and effort
Staff may not want to assume “added” responsibility without compensation
Lack of compensation
Hospital administration may not pay for antibiotic management without guaranteed pharmacy savings
Fear of antagonizing colleagues in other specialties
Damaged relations could lead to decreased request for consultation and lost income
In some hospitals, the pharmacy will not dispense certain antimicrobial agents without the approval of a physician trained in ID. This practice reduces both the use and costs of these agents. In several studies, this practice and other methods used to restrict antimicrobial use have decreased the incidence of certain drug-resistant organisms in healthcare settings.
IDSA’s Emerging Infections Network (EIN) surveyed its members to characterize antimicrobial restriction policies in their hospitals and the involvement of ID consultants in this process.
502 responded to the survey.
Almost all respondents agreed that inappropriate use of antibiotics is the most important factor contributing to increased antibiotic resistance.
Nearly all respondents agreed that ID consultants should be directly involved in the approval process of selected antimicrobials.
However, there are many barriers to the involvement of ID consultants in this process. Primary among these barriers are
Time and effort required to maintain an approval program
Lack of compensation for such a role
Fear of antagonizing colleagues from other specialties and consequent loss of income due to reduced consultations
In the editorial comment on this paper, John E McGowan, Jr identifies several stakeholder groups that must be included in efforts to deal with resistance in the healthcare setting. These groups include:
Prescribers
Patients
Healthcare administrators
Institutional thought leaders
Pharmacists, nurses, and laboratory personnel
Antimicrobial use improvement and quality assurance groups
Professional societies and the government
Sunenshine RH, et al. Clin Infect Dis 2004;38:

36. Conclusions
Antimicrobial stewardship can play a key role in the reduction of C difficile infection
Implementing successful stewardship programs involves multiple strategies, administrative support, and effective collaboration of a multidisciplinary team
Every ounce of stewardship counts – start small, think big!