Carbapenem resistant enterobacteriaceae cre and the imperative for antimicrobial stewardship
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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

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Carbapenem -resistant Enterobacteriaceae (CRE) and the Imperative for Antimicrobial Stewardship

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Carbapenem-resistant Enterobacteriaceae (CRE) and the Imperative for Antimicrobial Stewardship

Christopher Trabue, M.D.

September 13, 2013


  • Background and Epidemiology

  • Clinical significance and public health implications

  • Multipronged approach to controlling CRE in healthcare facilities

  • Antimicrobial stewardship

    • Our experience here

E. coli KlebsiellaEnterobacter



Enterobacteriaciae and beta lactam antibiotics

And the relationship therein


  • 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, intra-abdominal 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 antibiotic spectrum of these agents 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



No handwashing



How CRE evolved….

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

    • Acinetobacterbaumanii

    • 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 (ClinMicrobiol 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 NY hospitals this year: 5.4% (Infect Control HospEpidemiol. 2013 Aug;34(8):809-17)

TABLE 2. Number of Enterobacteriaceaeisolates reported — United States, National Nosocomial Infections Surveillance system, National Healthcare Safety Network

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: Case patients were more likely than control patients to die during hospitalization (48% vs 20%; P  .001) and to die from infection (38% vs 12%; P  .001).

Setting: Mount Sinai Hospital, a 1,171-bed tertiary care teaching hospital in New York City.

Design: Two matched case-control studies. 99 case patients, 99 controls.

Infect Control HospEpidemiol 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


  • 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….


Not commercially available

What comprises a stewardship program?

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

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


  • Clostridium difficilerates

  • Mean use of IV antibiotics

  • Provider-specific antibiotic prescribing rates

  • Total antibiotic charges


  • Study Period: February 20, 2013 – May 17, 2013

  • 172 patients met inclusion criteria for whom an intervention was indicated (297 total interventions)

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 difficilerates

    • 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

Study Quality




Relatively large number of patients, interventions, and antibiotic doses

Difficult to assign controls and comparison groups

Was observed effect truly due to our program?

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)


  • 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


  • 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 difficileinfection, and cost of healthcare

  • Our program here is a testament to how an ASP can be established successfully using existing resources

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