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Carbapenem-resistant Enterobacteriaceae
(CRE) and the Imperative for Antimicrobial
Stewardship
Christopher Trabue, M.D.
September 13, 2013
Outline
 Background and Epidemiology
 Clinical significance and public health implications
 Multipronged approach to controlling CRE in healthcare
facilities
 Antimicrobial stewardship
 Our experience here
E. coli MRSA
Klebsiella Enterobacter
VRE
Enterobacteriaciae and beta
lactam antibiotics
And the relationship therein
Enterobacteriaciae?
 Enterobacteriaciae refers to a large family of gram negative
bacilli that are commensal to the gastrointestinal tracts of
mammals




Escherichia coli
Klebsiella species
Enterobacter species
Proteus species
 Historically, these bacteria have been implicated in an array
of human infection (UTI, nosocomial pneumonia, intraabdominal infection) but have not been particularly
associated with the epidemic of multidrug resistance until
relatively recently
The clinical significance of beta lactam
antibiotics
 The beta lactam antibiotics comprise the penicillins,
cephalosporins, carbapenems, and monobactams (aztreonam)
 These agents easily comprise half of most hospital antibiotic
formularies
 Due to molecular innovations over the past 60 years, the
Aztreonam
antibioticPenicillin
spectrum ofCephalosporin
these agents Carbapenem
has been vastly
expanded
to cover a variety of different pathogens
Enterobacteriaciae – more and more
beta lactamase
 The primary mechanism of resistance for most
enterobacteriaciae to beta lactam antibiotics is through
enzymes known as beta lactamases
 These are a heterogeneous group of enzymes in that hydrolyze
(and thereby “open”) the beta lactam ring, inactivating it
CRE – an historical perspective
Thalidomide
Obstetricians:
No handwashing
Midwives:
Handwashing
How CRE evolved….
1940s – Penicillinase
1960s – Plasmid-mediated beta lactamase
1980s-90s – Extended-spectrum beta lactamase
(ESBL)
1996 – 1st reported CRE case in US (KPC –
Klebsiella pneumoniae carbapenemase)
2009 – 1st reported cases of New Delhi metalloβ-lactamase (NDM-1) reported in US
Carbapenems – why they matter
 Carbapenems are an essential component of the armamentarium
against many gram negative pathogens and serve as a last line of
defense
 Pseudomonas aeruginosa
 Acinetobacter baumanii
 ESBL-producing enterobacteriaciae
 What about other agents with different mechanisms of action (ie,
quinolones, aminoglycosides)?
 Many plasmid genes that encode carbapenemases also encode
resistance to other antimicrobials (Clin Microbiol Rev. 2005
Apr;18(2):306-25)
 In organisms with carbapenemases, resistance to other antimicrobials
is highly probable
The Emergence of CRE
The rise of the New Delhi metallo-β-lactamase and other CRE
CMAJ January 11, 2011 vol. 183 no. 1 59-64
NDM - Why India?
 In India, there is little restriction on antibiotics which can be
purchased cheaply without a prescription
 Ciprofloxacin is a commonly used antibiotic in India
 In India, pharmaceutical companies routinely discharge
byproducts of pharmaceutical agents into sewage
30X MIC for
many bacteria
CMAJ January 11, 2011 vol. 183 no. 1 59-64
CRE – increasing incidence
 The incidence of CRE has increased sharply over the past
decade
 The
point
prevalence
in two academic
NYreported
hospitals
TABLE
2. Number
of Enterobacteriaceae
isolates
— this year:
United
States, National
Infections Surveillance
5.4%
(Infect
ControlNosocomial
Hosp Epidemiol.
2013 Aug;34(8):809system, National Healthcare Safety Network
17)
CMAJ January 11, 2011 vol. 183 no. 1 59-64
CRE and mortality
 As is the case with many resistant organisms, infections due
to CRE are associated with significantly higher mortality
 Numerous studies have placed mortality due to these infections
in the 30-50% range
Results:
Setting:Case
Mount
patients
Sinaiwere
Hospital,
morealikely
1,171-bed
than
control
tertiary
patients
care teaching
to die during
hospitalhospitalization
in New York City.
(48%
Design:
vs 20%;
Two Pmatched
 .001)case-control
and to die from
studies.
infection
99
(38%
casevspatients,
12%; P99
 .controls.
001).
Infect Control Hosp Epidemiol 2008; 29:1099-1106
CRE – risk factors
 Transplant recipients
 Long term acute care hospitalization
 17.8% of LTACs reported at least 1 CRE-HAI versus 4.6% of
acute-care hospitals in 2012 (MMWR Morb Mortal Wkly Rep
2013; 62: 165–70.)
 Prior antibiotic therapy
 Beta lactam antibiotics
 Fluoroquinolones
CRE – treatment options
 Treatment options are limited to say the least
 Tigecycline
 Novel glycylcycline antibiotic
 Bacteriostatic, large volume of distribution (poor serum levels make it
less than ideal for bacteremic infections)
 Some data to suggest higher mortality in patients treated with this agent
over beta lactam agents
 Polymyxin B and E (Colistin)
 Older agent (approved in 1958)
 Potent, bacteriocidal activity
 Significant toxicity (primarily nephrotoxicity in the 50% range)
 There are numerous reports of CRE resistant to both agents
CRE and the challenge ahead
There is hope….
CRE and Infection Prevention:
Education
CRE and Infection Prevention:
Surveillance
CRE – Prevention Strategies
 Hand Hygiene
 Contact Precautions
 Minimizing use of devices
 Laboratory notification
 CRE screening
 Chlorhexidine bathing and intranasal mupirocin
 Antimicrobial Stewardship
423 references!
Antimicrobial Stewardship
Less is more….
What is ‘Antimicrobial Stewardship?’
 A process by which antimicrobial prescribing is optimized
and improved based on available evidence and guidelines
 Right agent/selection/combination/indication
 Right dose
 Right route
 Right duration
Why?
 In short, we are running
out of antibiotics
 Antimicrobial resistance is
far outpacing research,
development, and approval
of new antibiotics
 There is a lack of interest
among pharmaceutical
companies in developing
new antimicrobial agents
The Tennessean Nov 2011
Hitting home…. Our ICU….
And….
Not commercially
available
What comprises a stewardship
program?
Antimicrobial
Stewardship
Program
Physician
Clinical
Pharmacist
Support
IT
Clinical
Microbiology
Administrative and Community Support
What does a stewardship program do?
 Protocols and clinical pathways (ie CAP order set)
 Dose optimization and therapeutic drug monitoring for
vancomycin and aminoglycosides
 IV to PO conversion
 Active surveillance of hospital antibiotic use
 Prospective audit, feedback, and education
 De-escalation of therapy (ie, day 3 bundle)
 Integration with infection control and clinical microbiology (ie,
bug-drug mismatch)
 Formulary restriction and preauthorization
Is there data supporting stewardship?
 Yes. Lots.
 On all fronts….
 Patient outcomes
 Resistance
 C-diff
 LOS
 Cost
Antimicrobial Stewardship Team
Antimicrobial Expenditure Outcomes
White et al. 9
Hospital size, Primary ASP
strategy
575 beds, prior authorization
ID MDs and pharmacists
Gross et al.10
722 beds, prior authorization
ID MDs and ID-trained PharmD
Annual cost: $803,910; cost per patient-day
reduced from $18 to $14.40
Hospital cost after approval call: $6,468 vs.
$7,864 (P=0.08); cost attributable to
infection: $3,510 vs $4,205 (P=0.10); cost
attributable to antimicrobial agents: $79 vs
$122 (P=0.09)
Bantar et al.11
250 beds, concurrent review
ID
MD,
PharmD,
clinical
microbiologist,
laboratory
microbiologists, and data analyst
Cost-savings during the 18-month study
period: $913,236
Increased
cefepime
use
with
decreased
third
generation
cephalosporin and carbapenem use
correlated with drecreased resistance
Fraser et al.12
600 beds, concurrent review
ID MD fellow, critical care PharmD
Antimicrobial changes per patient significantly
less after intervention: $1,287.17 vs
$1,873.97 (P<0.04)
Not studied
Carling et al.13
174 bed community hospital,
concurrent review
ID MD and ID PharmD
Annual cost reduction: $200,000-$250,000
Reduced
rate
of
nosocomial
Clostridium
difficile
infection
(P=0.002) and infection due to drugresistant Enterobacteriaceae
LaRocco14
120 beds, concurrent review
ID MD, clinical pharmacist, IC, and
clinical microbiologist
Antibiotic cost per patient-day: reduced from
$18.21 to $14.77; annual expenditure
reduction: $177,000
No reported
Gentry et al.15
VA medical center, concurrent
review
ID PharmD, ID MD, and
microbiology laboratory director
Average annual reduction in intravenous
antimicrobial
expenditures:
30.8%
($145,942)
Not reported
650 total beds (22 in oncology
unit), concurrent review
ID MD, IC, and ID PharmD
Net savings for 1 year: $189,318
Reduced rate of VRE colonization and
bloodstream infection
Ozkurt et al.17
1200 beds, prior authorization
4 ID MDs
Annual savings: $322,000
Woodward
et
al.18
Philmon et al.19
1208 beds, concurrent review
Formulary restrictions
900 beds, prior authorization and
concurrent review
304 beds, education, and
guideline implementation
ID MD, clinical pharmacologist, and
microbiologist
ID MD and PharmD
Monthly savings for all antibiotics: $24,620
(P<0.03)
Total savings in acquisition costs during a 3year period: $1,841,203
Decrease in cumulative daily costs:
54%
Decrease in some drug-resistance
rates
Not reported
Reference
Montecalvo
al.16
Lutters et al.20
et
Drug Resistance and Infection
Control
Reduced resistance for several drugorganism pairings
Not studied
Decreased rate of
multiple antibiotics
Not reported
resistance
to
Summary of rationale
 Antimicrobial stewardship programs improve patient
outcomes
 Antimicrobial stewardship programs save money
 Antimicrobial stewardship programs are ineffective without
physician leadership and administrative support
 We are in the process of developing and implementing an
antimicrobial stewardship program (ASP) at Saint Thomas
Midtown Hospital
ASP Pilot
 In late 2012, with support from both URC and P&T, we
were asked by MEC to conduct a pilot study examining
antimicrobial stewardship at Saint Thomas Midtown Hospital
 Principle investigators for this effort: Christopher Trabue,
Ashley Tyler (clinical pharmacy specialist), Sharon Stacy
(medical affairs)
 The following criteria were developed for review:
 Review of all patients with positive blood cultures on the IMSB
service
 Review of all patients on the IMSB service on ≥ 2 antibiotics for
longer than 48 hours
 Review of all patients on the IMSB service on antibiotics for
longer than 7 days
ASP Pilot
 Exclusion
 ICU patients
 IMSB consult patients
 ID consult patients
 During the study, all recommendations were communicated
verbally to the attending physician if a change was recommended
 De-escalation or escalation
 Change
 Discontinue
 If a case was encountered where changes to therapy were
considered which were too complex for our program,
consultation was recommended
Metrics




Clostridium difficile rates
Mean use of IV antibiotics
Provider-specific antibiotic prescribing rates
Total antibiotic charges
Summary
 Study Period: February 20, 2013 – May 17, 2013
 172 patients met inclusion criteria for whom an intervention
was indicated (297 total interventions)
Issue
N
Intervention/Recommendation
Bug-drug mismatch
9
Antibiotics changed to appropriate therapy
Broad-spectrum therapy
with clinical
improvement
89
De-escalation to single agent
Adequate course of
antibiotics received
19
Antibiotics discontinued
No discernible infection
10
Antibiotics discontinued
Complicated issue, not
improving
15
Consultation
Preliminary Results
 Utilization rates for vancomycin, meropenem, IV and PO




ciprofloxacin, IV levaquin, and ceftriaxone declined
Utilization rates for piperacillin-tazobactam (Zosyn) were
essentially unchanged
Utilization rates for Levaquin PO increased
Improved cost associated with post-acute care (ie, more patients in
Pilot group discharged home, rather than to SNF)
Still in process:
 Clinical data – Sepsis/pneumonia/SSTI DRGs, attributable mortality,
changes in Clostridium difficile rates
 Provider-specific antibiotic prescribing rates
 Total antibiotic charges
Defined Daily Doses (DDD)
 Defined Daily Dose (DDD)
 Statistical measure used to estimate drug usage
 Defined by the World Health Organization (WHO)
 Defined Daily Dose (DDD) per 1,000 Patient Days
 Used to standardize DDDs based on patient census to allow for comparison over
time and with other hospitals
 Calculations
 DDD = Total grams of an antibiotic used per month
WHO DDD*
 WHO DDD is the average maintenance dose per day for a drug used for its main
indication in adults (e.g. WHO DDD for vancomycin is 2 grams)
 DDD per 1,000 patient days = DDD (from above calculation) x 1,000
Adult Inpatient Days
Meropenem (DDD/1000 Patient days)
60
56.27
48.40
50
40
30
20
10
0
2012
Pilot
Ceftriaxone (DDD/1000 Patient days)
50
47.00
45
40
35
32.88
30
25
20
15
10
5
0
2012
Pilot
Vancomycin IV (DDD/1000 Patient days)
160
140
135.90
118.02
120
100
80
60
40
20
0
2012
Pilot
Piperacillin-tazobactam (DDD/1000 Patient days)
60
57.96
57.20
2012
Pilot
50
40
30
20
10
0
Ciprofloxacin (DDD/1000 Patient days)
60
50
56.87
46.21
40
2012
30
Pilot
20
16.68
11.47
10
0
Ciprofloxacin IV
Ciprofloxacin PO
Levofloxacin (DDD/1000 Patient days)
50
45
40
44.57
41.08
35
29.34
30
25
20.98
20
15
10
5
0
Levofloxacin IV
Levofloxacin PO
2012
Pilot
Study Quality
Strengths
Weaknesses
 Prospective
 Difficult to assign controls
 Relatively large number of
and comparison groups
patients, interventions,
and antibiotic doses
due to our program?
 Was observed effect truly
 Short study period
ASP Summary
 The results of our pilot study were consistent with others’
experience with antimicrobial stewardship
 Identified patients on ineffective therapy (bug-drug mismatch),
and led to institution of appropriate therapy
 Reduced antimicrobial use and associated cost
 Drug cost (direct)
 Pharmacy and lab cost (vancomycin, aminoglycosides)
 Improved cost associated with post-acute care (ie, more patients
discharged home, rather than to SNF)
 Hopefully improved patient outcomes (data still pending)
Conclusions
 Carbapenem-resistant enterobacteriaciae have emerged as a




serious public health threat
The incidence of CRE is increasing globally, nationally, and
locally
Infections due to CRE are associated with poor outcomes
Risk factors for CRE include transplant history, LTAC stay,
and antibiotic use
Hand hygiene remains the most studied and most effective
means of reducing HAI
Conclusions
 Chlorhexidine bathing is also an effective means of reducing
HAI
 Antimicrobial stewardship is an effective means of reducing
unnecessary antibiotic use in hospitals, and the consequences
therein
 Antimicrobial stewardship programs have been shown to
reduce rates of antibiotic resistance, Clostridium difficile
infection, and cost of healthcare
 Our program here is a testament to how an ASP can be
established successfully using existing resources