Transcript The Role of Antimicrobial Stewardship in the Prevention of

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
Disclosures
• LD: No financial disclosures
• KL: No financial disclosures
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
Repeated antibiotics alter beneficial gut germs
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
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. 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 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%
• 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. 2005
Pepin J, et al. CMAJ. 2005
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;366:1079-1084
S Dial et al AMA. 2005 Dec 21;294(23):2989-95
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. 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
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; 353:2433-2441
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)
NNIS = National Nosocomial Infections Surveillance system
Carling P, et al. Infect Control Hosp Epidemiol. 2003;24:699-706.
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
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. 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 [email protected].
Antimicrobial Resistance is a
National Quality and Safety Issue
Antimicrobial Therapy
Appropriate initial
antibiotic while improving
patient outcomes and
heathcare
Unnecessary
antibiotics and adverse
patient outcomes and
increased cost
AntiMicrobial
Stewardship
A Balancing Act
•
•
•
•
•
•
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
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
Promoting optimal antimicrobial use
Reducing the transmission of infections
Building The Team
Infectious Diseases
Specialists
Infection Control
Administration
Clinical
Pharmacists
Antimicrobial
Control
OR Personnel
Microbiology
Pulmonary/
Intensivist
Nursing
Surgical Infection
Experts/Surgeons
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
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 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
60%
Utilization
50%
Figure 2. Description of Antimicrobial Restriction Methods
48%
43%
48%
46%
40%
40%
46%
34%
29%
30%
25%
16%
20%
8%
10%
0%
0%
Automatic Stop
Orders
ID Consult
Requirement
"Back End"
Approach
"Front End"
Approach
Approaches
Verbal Approval
With ASP
None
Without ASP
100%
Figure 1. Most Frequently Used Stewardship Strategies Other Than
Restriction Methods
85%
80%
Utilization
63%
60%
79%
60%
67%
65%62%
65%
48%
34%
40%
19%
20%
23%
0%
0%
Parenteral to
oral
conversion
Guidelines
and clinical
pathways
Dose
optimization
Closed
formularies
Strategies
Streamlining Antimicrobial Antimicrobial
or deorder forms
cycling
escalation
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!!!
Works well when used as a component in a ASP
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)
Computer Surveillance
•
•
•
•
•
•
Sentri7
SafetySurveillor-Pharmacy
TheraDoc
CPOE
Benchmarking
Antimicrobial use
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
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
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!