ASP Pilot

Christopher Trabue, M.D.September 13, 2013Carbapenem-resistant Enterobacteriaceae (CRE) and the Imperative for Antimicrobial Stewardship

OutlineBackground and EpidemiologyClinical significance and public health implicationsMultipronged approach to controlling CRE in healthcare facilitiesAntimicrobial stewardshipOur experience here

MRSAVREE. coli Klebsiella Enterobacter

Enterobacteriaciae and beta lactam antibioticsAnd the relationship thereinEnterobacteriaciae?Enterobacteriaciae refers to a large family of gram negative bacilli that are commensal to the gastrointestinal tracts of mammalsEscherichia coli Klebsiella speciesEnterobacter speciesProteus speciesHistorically, 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 antibioticsThe beta lactam antibiotics comprise the penicillins, cephalosporins, carbapenems, and monobactams (aztreonam)These agents easily comprise half of most hospital antibiotic formulariesDue 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

PenicillinCarbapenemCephalosporin

Aztreonam

The primary mechanism of resistance for most enterobacteriaciae to beta lactam antibiotics is through enzymes known as beta lactamasesThese are a heterogeneous group of enzymes in that hydrolyze (and thereby open) the beta lactam ring, inactivating it

Enterobacteriaciae more and more beta lactamase

CRE an historical perspective

Thalidomide

Obstetricians:No handwashingMidwives:HandwashingHow CRE evolved.Carbapenems why they matterCarbapenems are an essential component of the armamentarium against many gram negative pathogens and serve as a last line of defensePseudomonas aeruginosaAcinetobacter baumaniiESBL-producing enterobacteriaciaeWhat 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 CREThe rise of the New Delhi metallo--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 prescriptionCiprofloxacin is a commonly used antibiotic in IndiaIn 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 incidenceTABLE 2. Number of Enterobacteriaceae isolates reported United States, National Nosocomial Infections Surveillance system, National Healthcare Safety Network

CMAJ January 11, 2011 vol. 183 no. 1 59-64 The incidence of CRE has increased sharply over the past decadeThe point prevalence in two academic NY hospitals this year: 5.4% (Infect Control Hosp Epidemiol. 2013 Aug;34(8):809-17)

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.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).As is the case with many resistant organisms, infections due to CRE are associated with significantly higher mortalityNumerous studies have placed mortality due to these infections in the 30-50% rangeCRE and mortalityInfect Control Hosp Epidemiol 2008; 29:1099-1106

CRE risk factorsTransplant recipientsLong term acute care hospitalization17.8% of LTACs reported at least 1 CRE-HAI versus 4.6% of acute-care hospitals in 2012 (MMWR Morb Mortal Wkly Rep 2013; 62: 16570.)Prior antibiotic therapyBeta lactam antibioticsFluoroquinolones

CRE treatment optionsTreatment options are limited to say the leastTigecyclineNovel glycylcycline antibioticBacteriostatic, 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 agentsPolymyxin B and E (Colistin)Older agent (approved in 1958)Potent, bacteriocidal activitySignificant toxicity (primarily nephrotoxicity in the 50% range)There are numerous reports of CRE resistant to both agentsCRE and the challenge aheadThere is hope.

CRE and Infection Prevention: Education

CRE and Infection Prevention: Surveillance

CRE Prevention Strategies423 references!Hand HygieneContact PrecautionsMinimizing use of devicesLaboratory notificationCRE screeningChlorhexidine bathing and intranasal mupirocinAntimicrobial Stewardship

Antimicrobial StewardshipLess is more.What is Antimicrobial Stewardship?A process by which antimicrobial prescribing is optimized and improved based on available evidence and guidelinesRight agent/selection/combination/indicationRight doseRight routeRight durationWhy?In short, we are running out of antibioticsAntimicrobial resistance is far outpacing research, development, and approval of new antibioticsThere is a lack of interest among pharmaceutical companies in developing new antimicrobial agents

The Tennessean Nov 2011

Hitting home. Our ICU.

Not commercially availableAnd.

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What comprises a stewardship program?Administrative and Community SupportWhat does a stewardship program do?Protocols and clinical pathways (ie CAP order set)Dose optimization and therapeutic drug monitoring for vancomycin and aminoglycosidesIV to PO conversionActive surveillance of hospital antibiotic useProspective audit, feedback, and educationDe-escalation of therapy (ie, day 3 bundle)Integration with infection control and clinical microbiology (ie, bug-drug mismatch)Formulary restriction and preauthorizationIs there data supporting stewardship?Yes. Lots. On all fronts.Patient outcomesResistanceC-diffLOSCost43ReferenceHospital size, Primary ASP strategyAntimicrobial Stewardship TeamAntimicrobial Expenditure OutcomesDrug Resistance and Infection ControlWhite et al. 9575 beds, prior authorizationID MDs and pharmacistsAnnual cost: $803,910; cost per patient-day reduced from $18 to $14.40Reduced resistance for several drug-organism pairingsGross et al.10722 beds, prior authorizationID MDs and ID-trained PharmDHospital 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)Not studiedBantar et al.11250 beds, concurrent reviewID MD, PharmD, clinical microbiologist, laboratory microbiologists, and data analystCost-savings during the 18-month study period: $913,236Increased cefepime use with decreased third generation cephalosporin and carbapenem use correlated with drecreased resistanceFraser et al.12600 beds, concurrent reviewID MD fellow, critical care PharmDAntimicrobial changes per patient significantly less after intervention: $1,287.17 vs $1,873.97 (P