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AntibioticStewardship:“It’sAlsoAboutTheRightDiagnosis”

NeilGaffin,MDKimSimon,MSN,CIC,FAPIC

TheValleyHospitalRidgewood,NJ

Top7ThreatstotheHumanRace

2Source adapted from Science, Vol 325, September 2009Available at http://www.sciencemag.org/content/325/5948.cover-expansion

Remember These Days?WHO priority pathogens list for R&D of new antibiotic

February 27, 2017

Priority 1: CRITICAL

•Acinetobacter baumannii, carbapenem-resistant•Pseudomonas aeruginosa, carbapenem-resistant•Enterobacteriaceae, carbapenem-resistant, ESBL-producing

Priority 2: HIGH

•Enterococcus faecium, vancomycin-resistant•Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant•Helicobacter pylori, clarithromycin-resistant•Campylobacter spp., fluoroquinolone-resistant•Salmonellae, fluoroquinolone-resistant•Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant

Priority 3: MEDIUM

•Streptococcus pneumoniae, penicillin-non-susceptible•Haemophilus influenzae, ampicillin-resistant•Shigella spp., fluoroquinolone-resistant

Background: Impact

• Hospital-acquired, hospital-onset: 165,000 cases, $1.3 billion in excess costs, and 9,000 deaths annually

• Hospital-acquired, post-discharge (up to 4 weeks): 50,000 cases, $0.3 billion in excess costs, and 3,000 deaths annually

• Nursing home-onset: 263,000 cases, $2.2 billion in excess costs, and 16,500 deaths annually

Campbell et al. Infect Control Hosp Epidemiol. 2009:30:523-33. Dubberke et al. Emerg Infect Dis. 2008;14:1031-8.

Dubberke et al. Clin Infect Dis. 2008;46:497-504. Elixhauser et al. HCUP Statistical Brief #50. 2008.

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Background: EpidemiologyRisk Factors

• Antimicrobial exposure• Acquisition of C. difficile• Advanced age• Underlying illness• Immunosuppression• Tube feeds• ? Gastric acid suppression

Main modifiable risk factors

Date of download: 3/2/2017 © 2008 Infectious Diseases Society of America.

From: Antimicrobial-Associated Risk Factors for Clostridium difficile Infection

Clin Infect Dis. 2008;46(Supplement_1):S19-S31

BacterialCellsOutnumberUsBy10:1“Oral amoxicillin exposure caused marked shifts in microbiome composition that lasted approximately 30 days on average and were observed for more than 2 months in some of the treated individuals.

Large shifts were also reported during an oral course of ciprofloxacin, with the changes persisting for several weeks; the extent of restoration of the baseline composition of the microbiome was highly subject-dependent.”

Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4554–61.

“Collateral Damage” From Antibiotics

PLoS Pathog. 2015 Oct; 11(10): e1005157.

Developmental life cycle of Clostridium difficile during infection.

PLoS Pathog. 2015 Oct; 11(10): e1005157.

Effect of bile acid metabolism on the developmental life cycle of C. difficile.

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Genetic arrangement of the C. difficile pathogenicity locus and proposed protein domain structures of TcdA and TcdB.

Daniel E. Voth, and Jimmy D. Ballard Clin. Microbiol. Rev. 2005;18:247-263

TABLE 1. The Clinical Prediction Scale Variables Score

New-onset diarrhea 5Hospital length of stay beyond seven days 4Age over 65 years 3Long-term care facility resident 2High-risk antibiotics use* 1Hypoalbuminemia (<3 gm/dL) 1

*High-risk antibiotics include penicillins, cephalosporins, and fluoroquinolones.

Reference: Chandra et al J Clin Gastroenterol Volume 48, Number 5, May/June2014:420

Morbidity and Mortality Weekly Report

MMWR / January 13, 2017 / Vol. 66 / No. 1 33US Department of Health and Human Services/Centers for Disease Control and Prevention

Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae — Washoe County, Nevada, 2016

Lei Chen, PhD1; Randall Todd, DrPH1; Julia Kiehlbauch, PhD2,3; Maroya Walters, PhD4; Alexander Kallen, MD4

On August 25, 2016, the Washoe County Health District in Reno, Nevada, was notified of a patient at an acute care hospital with carbapenem-resistant Enterobacteriaceae (CRE) that was resistant to all available antimicrobial drugs. The specific CRE, Klebsiella pneumoniae, was isolated from a wound specimen collected on August 19, 2016. After CRE was identified, the patient was placed in a single room under contact precautions. The patient had a history of recent hospitalization outside the United States. Therefore, based on CDC guidance (1), the iso-late was sent to CDC for testing to determine the mechanism of antimicrobial resistance, which confirmed the presence of New Delhi metallo-beta-lactamase (NDM).

The patient was a female Washoe County resident in her 70s who arrived in the United States in early August 2016 after an extended visit to India. She was admitted to the acute care hospital on August 18 with a primary diagnosis of systemic inflammatory response syndrome, likely resulting from an infected right hip seroma. The patient developed septic shock and died in early September. During the 2 years preceding this U.S. hospitalization, the patient had multiple hospitalizations in India related to a right femur fracture and subsequent osteomyelitis of the right femur and hip; the most recent hospitalization in India had been in June 2016.

Antimicrobial susceptibility testing in the United States indi-cated that the isolate was resistant to 26 antibiotics, including all aminoglycosides and polymyxins tested, and intermediately resistant to tigecycline (a tetracycline derivative developed in response to emerging antibiotic resistance). Because of a high minimum inhibitory concentration (MIC) to colistin, the isolate was tested at CDC for the mcr-1 gene, which con-fers plasma-mediated resistance to colistin; the results were negative. The isolate had a relatively low fosfomycin MIC of 16 µg/mL by ETEST.* However, fosfomycin is approved in the United States only as an oral treatment of uncomplicated cysti-tis; an intravenous formulation is available in other countries.

A point prevalence survey, using rectal swab specimens and conducted among patients currently admitted to the same unit as the patient, did not identify additional CRE. Active surveillance for multidrug-resistant bacilli including CRE has been conducted in Washoe County since 2010 and is ongoing; no additional NDM CRE have been identified.

This report highlights three important issues in the control of CRE. First, although CRE are commonly sent to CDC as part of surveillance programs or for reference testing, isolates that are resistant to all antimicrobials are very uncommon. Among >250 CRE isolate reports collected as part of the Emerging Infections Program, approximately 80% remained susceptible to at least one aminoglycoside and nearly 90% were susceptible to tigecycline (2). Second, to slow the spread of bacteria with resistance mechanisms of greatest concern (e.g., gene encoding NDM or mcr-1) or with pan-resistance to all drug classes, CDC recommends that when these bacteria are identified, facilities ensure that appropriate infection control contact precautions are instituted to prevent transmission and that health care contacts are evaluated for evidence of transmission (3). Third, the patient in this report had inpatient health care exposure in India before receiving care in the United States. Health care facilities should obtain a history of health care exposures outside their region upon admission and consider screening for CRE when patients report recent exposure outside the United States or in regions of the United States known to have a higher incidence of CRE (1).

1Washoe County Health District, Nevada; 2University of Nevada, Reno, 3Nevada State Public Health Laboratory, 4Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, CDC.Corresponding author: Lei Chen, lchen@washoecounty.us, 775-328-2447.

References1. CDC. New carbapenem-resistant Enterobacteriaceae warrant additional

action by healthcare providers. Atlanta, GA: US Department of Health and Human Services, CDC; 2013. https://emergency.cdc.gov/han/han00341.asp

2. Guh AY, Bulens SN, Mu Y, et al. Epidemiology of carbapenem-resistant Enterobacteriaceae in seven U.S. communities, 2012–2013. JAMA 2015;314:1479–87. http://dx.doi.org/10.1001/jama.2015.12480

3. CDC. CRE toolkit: facility guidance for control of carbapenem-resistant Enterobacteriaceae (CRE). Atlanta, GA: US Department of Health and Human Services, CDC; 2015. https://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf

Notes from the Field

* http://www.biomerieux-diagnostics.com/etest.

Summary of Core Elements of Hospital Antibiotic Stewardship Programs

•Leadership Commitment: Dedicating necessary human, financial and information technology resources

•Accountability: Appointing a single leader responsible for program outcomes. Experience with successful programs show that a physician leader is effective

•Drug Expertise: Appointing a single pharmacist leader responsible for working to improve antibiotic use.

•Action: Implementing at least one recommended action, such as systemic evaluation of ongoing treatment need after a set period of initial treatment (i.e. “antibiotic time out” after 48 hours)

•Tracking: Monitoring antibiotic prescribing and resistance patterns

•Reporting: Regular reporting information on antibiotic use and resistance to doctors, nurses and relevant staff

•Education: Educating clinicians about resistance and optimal prescribing

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Source: CDC Vital Signs, August 2015

EmpiricAntibioticOrders

PositiveCultures/Definite

Infection

CulturesNegative/DefiniteInfection

CulturesNegative/NoObviousInfectionRequiringIVRx

IDMDSupervisedAutomaticNarrowing

ofAntimicrobialTherapy

DailyAssessmentofContinuedNeedforIVRxandAutomatic

ChangetoPOWhenAppropriate

DiscontinueTherapy

48HoursLater

TheValleyHospitalAntimicrobialStewardshipProcess.

ApprovedbyMedicalBoardDecember2013

Right drug, dose, time and duration, but it’s also about the right diagnosis.

Nursing Facility Stewardship

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2012AvgMonthly 1stQtr.2016AvgMonthly 2ndQtr.2016AvgMonthly 3rdQtr.2016AvgMonthly 9Months2016AvgMonthly Avg%ChangeinAntibiotic DaysofABXTherapy DaysofABXTherapy DaysofABXTherapy DaysofABXTherapy DaysofABXTherapy DaysofABXTherapy

CEFTRIAXONESODIUM(ROCEPHIN) 2387 725 732 758 738 -69.08%CEFAZOLINSODIUM(KEFZOL) 257 309 304 300 304 18.29%METRONIDAZOLE/SODIUMCHLORIDE(FLAGYLIVPB) 670 325 372 394 364 -45.67%VANCOMYCINHCL(VANCOCIN) 640 229 244 297 257 -59.84%AMPICILLINSODIUM/SULBACTAMNA(UNASYN) 109 151 178 178 169 55.30%AZITHROMYCIN(ZITHROMAXINJ) 468 144 127 86 119 -74.57%PIPERACILLINSODIUM/TAZOBACTAM(ZOSYNVIAL) 279 79 89 80 83 -70.25%LEVOFLOXACIN/D5W(LEVAQUINIVPB) 165 71 62 62 65 -60.61%AZTREONAM(AZACTAM) 260 86 69 81 79 -69.62%

Avg%ChangeAveragePatientDays 10,458 9,477 8,378 9,053 8,969 -9.40%

AverageTotalDaysofAntibioticTherapy 5,235 2,119 2,177 2,236 2,177 -58.41%

AntibioticDaysofTherapy/1000PatientDays 501 232 260 247 243 -51.50%

AntibioticCostperPatientDay2012 $14.20 $5.26 $5.20

DaysofAntibioticTherapy

“Things are not always what they seem; the first appearance deceives many; the intelligence of a few perceives what has

been carefully hidden”

Phaedrus

The Major Culprits Contributing To Overuse Pneumonia is a Clinical Diagnosis-A Chest X-Ray alone Can’t Diagnose It

AntibioticsDiscontinued

IsolatedFever-NoPulm Sx’s Post- Seizure&MI

TransitionsofCare-TheDoortoUnnecessaryDOT

• First,wehavetoensurethattheoriginaldiagnosiswascorrect-don’tjusttakethediagnosisonfacevalue!Manyinfectiousdiagnosesareincorrect,inparticular“pneumonia”,“UTI”,and“cellulitis”.

• Second,wehavetorealizethatmosttypicalinfectionscanbetreatedeffectivelywith5-7daysoftherapy,orwhenclinicalsignsandsymptomshaveresolved(couldbesooner!!).

• Third,sincetheaverageLOSatacutecarefacilityis4daysroughly,thenwe’repotentiallytalkingaboutonly0-3moredaysoftherapyuponarrivalattheSNF!

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Beware!The“UTI”Problem

“Insanityisdoingthesamethingoverandoverandexpectingdifferentresults.”AlbertEinstein

The Urine Problem

Under normal conditions…

the skin surface is not sterile…

the mouth is not sterile…

the colon is not sterile…

and in many patients,

the bladder is not sterile.

Asymptomatic Bacteriuria

• Positive urine culture, but no need for antibiotic treatmentExceptions:

- Pregnancy

- Prior to urologic surgery

Nicolle LA, et al. IDSA Guidelines for Asymptomatic Bacteriuria. CID 2005: 40( March 1); 643-654

Prevalence-Asymptomatic Bacteriuria

Population Prevalence

Long-term care facility, age ≥70Women 25-50%Men 15-40%

Community, age ≥70Women 11-16%Men 4-19%

Healthy pre-menopausal women 1-5%

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Nicolle LA, et al. IDSA Guidelines for Asymptomatic Bacteriuria. CID 2005: 40( March 1); 643-654

Population Percentage(%)

YoungWomen 32

PregnantWomen 30-70

DiabeticWomen 70

ElderlyInstitutionalized 90

Hemodialysis 90

Bacteriuric Short–TermCatheters 30-75

Bacteriuric Long-TermindwellingCatheters 50-100

Nicolle LA, et al. IDSA Guidelines for Asymptomatic Bacteriuria. CID 2005: 40( March 1); 643-654

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ASBIsA MarkerForVulnerability

• 318womenwithASBolder,sickerandhadgreatermortalitythan1173womenwithoutASB.

• Multivariateanalysis-ASBunrelatedtomortality.• TreatmentofASBhadnoeffectonmortality.

Abrutyn, Ann Int Med 1994

Beware!“ThePneumoniaConundrum”• Thestandardfordiagnosingpneumoniathathasdevelopedoverthepast

severaldecadesinvolvesrecognitionofasyndromeofclinical,laboratoryandradiographicfeaturescompatiblewithpulmonaryinfection.

• PatientswithnonspecificCXRopacitiesbutwithoutclinicalfeaturessuggestiveofpulmonaryinfectionshouldnotbereflexivelydiagnosedwithpneumoniaandtreatedwithantibiotics.

• InthisstudyofadultEDpatientspresentingwithacutecardiopulmonarysymptoms,6.6%ofpatientshadpulmonaryopacitiesinterpretedonCXRthatwerenotreproducedonCT.Consideringthe12.4millionEDvisitsannuallyintheUSduetoshortnessofbreath,chestpainorcough,an“opacityequalsantibiotics”reflexivemanagementstrategyislikelytoleadtofrequentoveruseofantibioticsandunnecessarypressureforthedevelopmentofantibioticresistance.

1. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44(Suppl 2):S27–S72.

2. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA. 1997; 278:1440–1445.

3.High Discordance of Chest X-ray and CT for Detection of Pulmonary Opacities in ED Patients: Implications for Diagnosing Pneumonia Wesley H. Self, MD MPHa Am J Emerg Med. 2013 February ; 31(2): 401–405

Procalcitonin-CouldPotentiallyHelpUsGetPatientsOffAntibioticsSooner

• TheUSFoodandDrugAdministration(FDA)hasclearedtheexpandeduseoftheVidas Brahmsprocalcitonin (PCT)testtohelpcliniciansdeterminewhetherantibiotictreatmentshouldbeinitiatedorstoppedinpatientswithlowerrespiratorytractinfectionsandstoppedinpatientswithsepsis.

Beware!“TheCellulitisProblem”

• It'spurelyaclinicaldiagnosis,almostalwaysofacuteonsetandunilateral.

• Inflammatorydermatosesofthelowerextremityareoftenmisdiagnosedascellulitis(aka“pseudocellulitis”)andtreatedwithantibioticsand/orhospitalization.Thereislimiteddataonthecostandcomplicationsfrommisdiagnosedcellulitis.

• Inthiscross-sectionalstudythatincluded259patients,30%weremisdiagnosedwithcellulitis,ofwhich85%didnotrequirehospitalizationand92%receivedunnecessaryantibiotics.Combiningthesefindingswithpreviouslypublisheddata,costestimates,andandprojectionsindicatethatcellulitismisdiagnosisleadsto50 000to130 000unnecessaryhospitalizationsintheUnitedStatesand$195millionto$515millioninavoidablehealthcarespendingannually.

JAMA Dermatol. 2017;153(2):141-146.

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