The Role of Antimicrobial Stewardship in the Prevention of

Clostridium Difficile Infections

Kenneth Lawrence, PharmDLisa Davidson, MD

Tufts Medical CenterDepartment of Pharmacy

Division of Geographic Medicine and Infectious Disease

Disclosures

• LD: No financial disclosures• KL: No financial disclosures

The microbiome….

• Microbes account for 60% of the Microbes account for 60% of the earth’s biomassearth’s biomass

• Microbes are ancient and have been Microbes are ancient and have been in existence for 350 million yearsin existence for 350 million years

• There are 5-10 times more bacteria There are 5-10 times more bacteria living on or in a human than human living on or in a human than human cellscells

Repeated antibiotics alter beneficial gut germs

Colonizers vs Pathogens

• The majority of bacteria that live in and on humans The majority of bacteria that live in and on humans areare colonizerscolonizers, living in a delicate balance with their , living in a delicate balance with their human host that has evolved of millions of years.human host that has evolved of millions of years.

• Pathogens Pathogens are microbes that depend upon a are microbes that depend upon a pathogenic relationship with their hosts for survival.pathogenic relationship with their hosts for survival.

• By using invasive properties, such as toxins and By using invasive properties, such as toxins and virulence factors, these pathogenic bacteria virulence factors, these pathogenic bacteria establish a niche that is devoid of competition from establish a niche that is devoid of competition from other nonpathogenic microbes.other nonpathogenic microbes.

Falkow, 2005; IOM 2006

Clostridium difficileClostridium difficile• Anaerobic spore-forming bacillusAnaerobic spore-forming bacillus

– Transmission of spores in vegetative stateTransmission of spores in vegetative state– Fecal-oral transmission Fecal-oral transmission

• In 1978, In 1978, C difficile C difficile was identified as the major cause of was identified as the major cause of Antibiotic-associated diarrhea Antibiotic-associated diarrhea – Multiple studies have demonstrated the association of Multiple studies have demonstrated the association of

CDI and antimicrobials CDI and antimicrobials • 96% of patients with CDI received antimicrobials 96% of patients with CDI received antimicrobials

within the 14 days within the 14 days • Prior to 2000: The majority of CDI were nosocomialPrior to 2000: The majority of CDI were nosocomial• Presentation ranged from symptomless carriage, to mild or Presentation ranged from symptomless carriage, to mild or

moderate diarrhea, to fulminant and sometimes fatal moderate diarrhea, to fulminant and sometimes fatal pseudomembranous colitispseudomembranous colitis

L Mcdonald. Emerg Infect Dis. 2006 Mar;12(3):409-15.;MM Olson et al. Infect Control Hosp Epidemiol 1994;15:371–381.

CDI Mortality Rates per million Population, US, 1999–2004

Redelings MD, et al. Emerg Infect Dis 2007;13:1417-19

Clostridium difficileClostridium difficile: a new strain emerges: 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%• 2000-2001: 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. 2005Pepin J, et al. CMAJ. 2005

Clostridium difficileClostridium difficile: a new strain emerges: a new strain emergesStrain NAP1/BI/027Strain 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;366:1079-1084S Dial et al AMA. 2005 Dec 21;294(23):2989-95

Antibiotics and CDIAntibiotics 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. 1997 Nov;40(5):707-11.; Aliment Pharmacol Ther. 1998 Dec;12(12):1217-23. J Hosp Infect. 2003 Jun;54(2):104-8.; Infect Control Hosp Epidemiol. 1994 Feb;15(2):88-94.

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; 353:2442-2449; Muto et al Infect Control Hosp Epidemiol 2005;26:273–280; Clinical Infectious Diseases 2004;38:640–64

Is there a solution?

• ““Finally, an important method of controlling past Finally, an important method of controlling past outbreaks of outbreaks of C. difficileC. difficile–associated disease has been –associated disease has been restriction of the use of antimicrobial agents implicated restriction of the use of antimicrobial agents implicated as risk factors for the disease…. … Because as risk factors for the disease…. … Because fluoroquinolones have become a mainstay in the fluoroquinolones have become a mainstay in the treatment of several common infections, a large-scale treatment of several common infections, a large-scale restriction of the use of these drugs would be quite restriction of the use of these drugs would be quite difficult…..it will be important either to reconsider the difficult…..it will be important either to reconsider the use of fluoroquinolones or to develop other innovative use of fluoroquinolones or to develop other innovative measures for controlling measures for controlling C. difficileC. difficile–associated –associated disease.”disease.”

L Mcdonald, et al. N Engl J Med 2005; 353:2433-2441

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)

Carling P, et al. Infect Control Hosp Epidemiol. 2003;24:699-706.

NNIS = National Nosocomial Infections Surveillance system

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 = 0.009 )

Fowler S et al. J. Antimicrob. Chemother. 2007;59:990-995

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 2003-2004 to 2005-2006, 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. 2007 Sep 1;45 Suppl 2:S112-21.

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 Acquisition rates in patients hospitalized for CAP in a low endemic regionendemic region

• Nosocomial acquisition rate of Nosocomial acquisition rate of C. difficileC. difficile carriage was carriage was 11.2%. No nosocomially acquired CDI occurred. 11.2%. No nosocomially acquired CDI occurred.

• Acquisition rates of Acquisition rates of C. difficile carriage C. difficile carriage (P = 0.84):(P = 0.84):– 11.9% (5/45) in moxifloxacin11.9% (5/45) in moxifloxacin– 11.1% (5/47) in beta-lactam11.1% (5/47) in beta-lactam– 9.0% (1/14) in beta-lactam plus macrolide- or 9.0% (1/14) in beta-lactam plus macrolide- or

fluoroquinolone-treated patientsfluoroquinolone-treated patients• Risk factors for C. difficile carriage:Risk factors for C. difficile carriage:

– antibiotic treatment >7 days [odds ratio (OR) 3.89; 95% antibiotic treatment >7 days [odds ratio (OR) 3.89; 95% confidence interval (CI) 1.30 to 11.79]confidence interval (CI) 1.30 to 11.79]

– hospitalization during the past 3 months (OR 4.08; 95% hospitalization during the past 3 months (OR 4.08; 95% CI 1.40 to 11.90). CI 1.40 to 11.90).

J Antimicrob Chemother. 2010 Sep 7. [Epub ahead of print]

From Infect Control Hosp Epidemiol  31(10):1030-1037. © 2010 by The Society for Healthcare Epidemiology of America. All rights reserved. For permission to reuse, contact journalpermissions@press.uchicago.edu.

Antimicrobial Resistance is a National Quality and Safety Issue

A Balancing ActA Balancing ActA Balancing ActA Balancing Act

Appropriate initial antibiotic while improving patient

outcomes and heathcare

Appropriate initial antibiotic while improving patient

outcomes and heathcare

Unnecessaryantibiotics and adverse patient outcomes and

increased cost

Unnecessaryantibiotics and adverse patient outcomes and

increased cost

Antimicrobial Therapy

Anti-Anti-MicrobialMicrobial

StewardshipStewardship

• Enterococcus• S. aureus• Klebsiella spp.• Acinetobacter• P. aeruginosa• Enterobacter spp.

Boucher H, et al, Clin Infect Dis 2009;48:1-12Patterson, et al, Clin Infect Dis 2009;49:992-3

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

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.

Dellit TH, et al. CID 2007;44:159-77, Hand K, et al. Hospital Pharmacist 2004;11:459-64Paskovaty A, et al IJAA 2005;25:1-10

Ultimate goal is improved patient care and Ultimate goal is improved patient care and healthcare outcomeshealthcare outcomes

Promoting optimal antimicrobial useReducing the transmission of infections

Building The Team

Infectious Diseases Specialists

AntimicrobialAntimicrobialControlControl

AntimicrobialAntimicrobialControlControl

Infection Control Administration

ClinicalPharmacists

Nursing

Surgical InfectionExperts/Surgeons

OR Personnel

Microbiology

Pulmonary/Intensivist

Antimicrobial Stewardship Strategies

• Front end: Formulary restriction and preauthorization• Back end: Interventions after antimicrobials have been

prescribed• BOTH: Prospective audit with intervention and feedbackSupplemental 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;11:459-64Paskovaty A, et al IJAA 2005;25:1-10

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

“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

“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

Survey of Antimicrobial Stewardship PracticeSurvey of Antimicrobial Stewardship Practice

• 39% of respondents had an ASP 39% of respondents had an ASP • 92% of institutions with an ASP had an ID consult service, 92% of institutions with an ASP had an ID consult service,

compared to only 66% of institutions without an ASP.compared to only 66% of institutions without an ASP.• ASP institutions measured effectiveness of their programs by ASP institutions measured effectiveness of their programs by

antimicrobial expenditures (58%), antimicrobial resistance antimicrobial expenditures (58%), antimicrobial resistance (52%) and frequency of physician acceptance (50%). (52%) and frequency of physician acceptance (50%).

• 80% of all participating hospitals used antimicrobial order 80% of all participating hospitals used antimicrobial order restriction as the most common techniquerestriction as the most common technique

Median yearly antimicrobial expenditures for antibacterials and Median yearly antimicrobial expenditures for antibacterials and antifungals was $1.35 million for institutions antifungals was $1.35 million for institutions withwith an ASP, versus an ASP, versus $800,000 for institutions $800,000 for institutions withoutwithout an ASP an ASP

75% of participants from institutions with an ASP stated 75% of participants from institutions with an ASP stated physicians at their institutions agreed with the antimicrobial physicians at their institutions agreed with the antimicrobial restrictions, versus only 46.6% at institutions restrictions, versus only 46.6% at institutions withoutwithout an ASP an ASP

Nadarki et al. SHEA 2010

Figure 2. Description of Antimicrobial Restriction Methods

46%

0%

25%

46%48% 48%

16%

8%

34%40%43%

29%

0%

10%

20%

30%

40%

50%

60%

Automatic StopOrders

ID ConsultRequirement

"Back End"Approach

"Front End"Approach

Verbal Approval None

Approaches

Uti

lizat

ion

With ASP Without ASP

Figure 1. Most Frequently Used Stewardship Strategies Other Than Restriction Methods

48%

0%

79%

65%65%67%

85%

34%

62%

19% 23%

63% 60%

0%

20%

40%

60%

80%

100%

Parenteral tooral

conversion

Guidelinesand clinicalpathways

Doseoptimization

Closedformularies

Streamliningor de-

escalation

Antimicrobialorder forms

Antimicrobialcycling

Strategies

Uti

liza

tion

With ASP Without ASP

Educational Strategies

– Point Prevalence Surveys

– Newsletter

– Posters

– Guideline dissemination and guidebooks

– Nursing in-services, Grand rounds and other conferences

• AMT Champion

– E-mail: Question of the week

Infrequently successful alone!!!Infrequently successful alone!!!Works well when used as a component in a ASPWorks well when used as a component in a ASP

More on the Back end: Getting your pharmacist really excited…

• Automatic IV to PO conversionAutomatic IV to PO conversion• Automatic Drug conversionAutomatic Drug conversion

– Ex: transfers from outside hospital – get on Ex: transfers from outside hospital – get on formulary drugsformulary drugs

• Alternative dosing regimensAlternative dosing regimens– Continuous or prolonged infusions of Continuous or prolonged infusions of ß-lactamß-lactam

– Increased frequency of dosing (e.g, meropenem)Increased frequency of dosing (e.g, meropenem)

Computer Surveillance

• Sentri7• SafetySurveillor-Pharmacy• TheraDoc• CPOE• Benchmarking• Antimicrobial use

The government vs. the microbesThe 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

http://www.cms.hhs.gov/

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

Sunenshine RH, et al. Clin Infect Dis 2004;38:934-38.

Conclusions

• Antimicrobial stewardship can play a key role in Antimicrobial stewardship can play a key role in the reduction of the reduction of C difficileC difficile infection infection

• Implementing successful stewardship programs Implementing successful stewardship programs involves multiple strategies, administrative involves multiple strategies, administrative support, and effective collaboration of a support, and effective collaboration of a multidisciplinary teammultidisciplinary team

• Every ounce of stewardship counts – start small, Every ounce of stewardship counts – start small, think big!think big!