Prevention of Multiple-Drug Resistant Gram Negative Rod

(MDR-GNR) Infections

Daniel J. Diekema, MD, D(ABMM)Professor and Director

Division of Infectious DiseasesUniversity of Iowa Carver College of Medicine

E-mail: daniel-diekema@uiowa.edu

Disclosures: Research funding from bioMerieux, Cerexa, Innovative Biosensors, T2 Biosystems, Pfizer, and PurThread Technologies

Objectives

• Review the threat of MDR-GNR• Apply methods to prevent the

emergence, transmission, and infection with MDR-GNRs

Trying to find answers in the absence of controlled trial data.

Peleg and Hooper. N Engl J Med 2010;362:1804-13.

What is an MDR-GNR?• No uniform definition

• Resistance to 3 or more of the major antimicrobial classes used for treatment

• The greatest current threats:– Beta-lactamase producers

• ESBLs of all types• Carbapenemases (CRE: KPC, NDM, IMP, etc.)

– Multiple drug-resistant non-fermenters• Acinetobacter, Pseudomonas, Stenotrophomonas

% MDR among CLABSI GNRs NHSN 2009-2010

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E. coli Enterobacter P.aeruginosa

Klebsiella Acinetobacter

% MDR

Sievert DM, Ricks P, et al. Infect Cont Hosp Epidem 2013;34:1-14.

Resistance to 3 or more major classes used to treat….

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MDR-Acineto Acineto Uninfected

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Crude mortality LOS

Acinetobacter: Impact of MDR

N = 96, 91, 89 Sunenshine et al. Emerg Infect Dis 2007;13:97-103.

MDR-GNR outbreaks are the worst!

• Systematic review of over 1500 hospital outbreaks over 40 years– Unit closure required more often with MDR-GNR

• e.g. NIH Clinical Center outbreak, nationwide outbreak of KPC in Israel

• Extensive and persistent environmental contamination, prolonged human carriage, multidrug resistance likely all play a role

Hansen S, et al. J Hosp Infect 2007;65;348.Snitkin et al. Sci Transl Med 2012;4:148ra116.

Antimicrobial StewardshipHand HygieneEnvironmental disinfection

Contact precautions*Cohorting*

MDRO Prevention Approaches

Decolonization*SSI, BSI, VAP, UTI prevention

3. Preventing infection among those colonized

1. Preventing emergence under antimicrobial pressure

2. Preventing transmission

*may be guided by active surveillance cultures

Preventing Emergence Under Antimicrobial Pressure

Is antimicrobial exposure a risk for MDR-GNR (CRE)?

• Case-Control study at Detroit Med Center

• Cases: Clinical cultures + for CRE (N, 91)

• Controls: 1. ESBL, 2. non-ESBL, 3. None

• Antibiotic exposure in prior 3 months was the ONLY variable consistently associated with CRE, regardless of comparison group selected

Marchaim D, et al. Infect Cont Hosp Epidemiol 2012;33:817-830.

Improved PSA susceptibility after a stewardship intervention

Yong MK, et al. J Antimicrob Chemother 2010;65:1062-69.

AMS and MDR-GNR: Summary

• Antimicrobial use is a risk factor for MDR-GNR isolation and infection (CRE)

• Reducing antimicrobial use has been temporally associated with decreased resistance

• More research needed on impact of antimicrobials on MDR-GNR carriage/infxn

Preventing Transmission

Semmelweis was right!

Kirkland KB, et al. BMJ Qual Saf 2012;21:1019

Acinetobacter: Easily spread from patient to HCW

• 199 episodes of care of MDR-Acineto patients (in CP)

• 77 (38%): + gloves or gowns• 9 (4.5%) on hands after glove

removal• Higher rates than for

Pseudomonas, MRSA or VRE

Morgan et al. Infect Cont Hosp Epidemiol 2010;31:716-721.

Are all MDR-GNR created equal?

• Active screening of room contacts of patients colonized/infected with ESBL

• Mostly E. coli carrying CTX-M

• Transmission in only 2 of 133 contacts

• Community rates of CTX-M rising

• ? Need for contact precautions in non-outbreak setting

Tschudin-Sutter, et al. Clin Infect Dis 2012;55:1505-11.

How effective are contact precautions in preventing transmission of MDR-GNRs?

• Unknown

• Ineffective if adherence is poor (20-30%)– Afif W, et al. Am J Infect Control 2002;30:430-433– Cromer AL, et al. Am J Infect Control 2004;32:451-5

• Most data from outbreak settings

• Given extent of environmental contamination with some MDR-GNRs, barrier precautions make theoretical sense

Roles of Active Surveillance for a MDR-GNR

• Targeted surveillance of high risk patients:– Useful during outbreaks and when incidence

of an MDR-GNR is rising despite routine control efforts (Tier 2 recommendation)

• Point prevalence surveys during outbreaks:– Define reservoir and guide control efforts– Determine if on-going surveillance cx needed

CDC/HICPAC MDRO guideline.

Undetected fraction during a hospital-wide outbreak of KPC

• Rectal screening cultures on all high risk units• Overall colonization rate = 9%

– 4% admit → 12% at 48-hours

• 52% of colonized/infected pts detected only by surveillance cultures [Undetected fraction]

• Outbreak resolved (6.9 → 1.8 cases/10K) after multifaceted intervention

Ben-David D, et al. Infect Cont Hosp Epidemiol 2010;31:620-26.

Sensitivity (%) of each body site for detecting MDR-GNR colonization

Weintrob, et al. Infect Cont Hosp Epidemiol 2010;31:330-337.

Anatomic site Acineto E. coli KPN All

Groin area 73 71 100 84

Perirectal 29 80 67 50

Other skin sites <30 <14 <50 <28

Groin + perirectal 82 100 100 95

Detecting KPC-producing Enterobacteriaceae in LTACH patients

Thurlow, et al. Infect Cont Hosp Epidemiol 2013;34:56-61.

Anatomic site Sensitivity (%)

Back/antecubital fossa 25

Oropharyngeal 42

Urine 53

Axillary 75

Inguinal 79

Rectal 88

Rectal + inguinal 100

Environmental Contamination with MDR-GNRs

• Bed rails• Bedside tables• Ventilators• Infusion pumps• Mattresses• Pillows• Air humidifers• Patient monitors

• X-ray view boxes• Curtain rails• Curtains• Equipment carts• Sinks• Ventilator circuits• Floor mops• Keyboards

Environmental Survival of Gram Negatives

Survival of different bacteria when dried on stainless steel

Acinetobacter

Klebsiella

Kramer A, et al. BMC Infectious Diseases 2006;6:130

Association between environmental and patient isolates of Acinetobacter

Denton M, et al. J Hosp Infect 2004;56:106-110.

During a 14 month, 19 patient outbreak.All had same PFGE pattern.

Hazards of the prior room occupantIndependent Risk Factors OR (95% CI) P-value

MDR PSA (N=82)

Prior occupant 2.3 (1.2-4.3) 0.01

Surgery 1.9 (1.1-3.6) 0.02

Prior Pip Tazo 1.2 (1.1-1.3) 0.04

Acinetobacter (N=57)

Prior occupant 4.2 (2-9) <0.001

Mech ventilation 9.3 (1.1-83) 0.0045

ESBL-producer (N=50)

Tracheostomy 2.6 (1.1-6.5) 0.049

Sedation 6.6 (1.1-40) 0.041

MV model included colonization pressure, among other RFs.Nseir et al. Clin Microbiol Infect 2011;17:1201-08.

Cleaning interventions

36 hospitals, fluorescent targeting method. Carling et al. ICHE 2008;29:1035-41.

Routine cleaning and disinfection (C/D) vs H2O2 vapor (HPV)

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AcinetobacterMRSA

Manian F, et al. Infect Cont Hosp Epidemiol 2011;32:667-72.

No touch methods: How effective?

• Reduction in bioburden c/w conventional cleaning & disinfection (C/D)

• ↓ risk of VRE acquisition from prior room occupant when used for terminal cleaning– 80% risk reduction (6% absolute reduction)– No significant reduction for other MDROs

• Performance improved C/D shows similar results for both MRSA and VRE

Passaretti, et al. Clin Infect Dis 2013;56:27-35.Datta, et al. Arch Intern Med 2011;171:491-94.

“Evidentiary hierarchy”

for new technologies

McDonald and Arduino.

Clin Infect Dis 2013;56:36-39

Preventing Transmission:Summary

• Focus on HAND HYGIENE– Likely to be the final common pathway

• Contact (barrier) precautions for those known to carry MDR-GNR

• Enhanced environmental disinfection– Education and observation/feedback– New technologies? Need more outcome data

• Practical issues (e.g. cost, room turnover)

Preventing Infection Among those Colonized

How often do MDR-GNR carriers develop infection?

• Likely to vary by organism and host

• Screening study of ICU admissions

• 2% of 11,236 patients were KPC carriers

• 46% of carriers also had + clinical culture

• 27% of carriers had BSI due to KPC

Calfee and Jenkins. Infect Cont Hosp Epidemiol 2008;29:966-68.

Which KPC carriers get infected?

• Matched case-control study in Tel Aviv

• 44 Cases: CRE carriers with clinical cx +

• 88 Controls: CRE carriers with no + cx

Variable OR (95% CI) P

ICU stay 7.5 (1.3-42) 0.02

CVC 5.7 (1.4-23) 0.02

Antibiotics 3.3 (1.1-9.7) 0.04

Diabetes 2.8 (1.1-7.0) 0.03

Schechner V, et al. Clin Microbiol Infect 2012;1-6.

How long does colonization with MDR-GNR persist? A long time

O’Fallon E, et al. Clin Infect Dis 2009;48:1375-81.

What about selective digestive decontamination (S-DD)?

Gentamicin + Polymyxin X 7d

Saidel-Odes L, et al. Infect Cont Hosp Epidemiol 2012;33:14-19.

Chlorhexidine bathing to reduce MDR A. baumannii?

• Quasi-experimental, before-after design

• Attack rate of A. baumannii

– BSI: 4.6% => 0.6% (OR=7.6, p<.001)

• Incidence density of A. baumannii

– BSI: 7.8 to 1.25/1000 pt-days (85% ↓)– Borer et al. J Hosp. Infect 2007; 67:149-55

• ↓colonization in comparative study– Evans et al. Arch Surg 2010;145:240-46.

Chorhexidine bathing reduces HA-BSI, MDRO acquisition….

Organism Treatment arms Control arms

Gram positive (all) 63 125

Coag-negative staphylococcus 30 72

Enterococcus spp 20 35

Staphylococcus aureus 12 12

Gram negative (all) 33 40

Climo et al. N Engl J Med 2013;368:533-42.Milstone et al. Lancet 2013;January 25.

Two randomized controlled crossover trials (pediatric and adult ICUs)The difference is mostly among the gram-positive organisms (CoNS)

Chlorhexidine resistance among KPC-producing KPN

126 MDR strains tested, ST258 had highest MICs

Naparstek et al. J Hosp Infect 2012;81:15-19.

Preventing infection in those colonized with MDR-GNR: Summary

• Focus on the basics!– reducing CLABSI, VAP, CAUTI, SSI– most infections in sicker/ICU/CVC patients

• There is no known effective “decolonization” regimen for MDR-GNRs

• Chlorhexidine may be effective at reducing infection/transmission risk– May be limited in future by resistance

“Bundled” approaches to preventing MDR-GNR infections

(Outbreak response)

• Hand hygiene with real time monitoring• Enhanced contact isolation of all ICU patients• Cohorting of KPC-positive pts, and all staff• Active surveillance cultures (ICU + PP surveys)• Visitor and staff restrictions• Dedicated single use devices• Bleach double-cleaning of rooms

• H2O2 vapor for KPC-patient roomsScience Trans Med 2012;4:148ra116

KPC bundle in an LTACH

• Daily 2% chlorhexidine baths

• Enhanced environmental cleaning

• Active surveillance upon admission

• Serial point prevalence surveys

• Contact isolation of carriers

• Training of healthcare personnel

Over 6 months, KPC transmission was prevented despite ongoing admission of KPC carriers.

Munoz-Price, et al. Infect Cont Hosp Epidemiol 2010;31:341-347.

Nationwide outbreak, Nationwide responseKPC- K. pneumoniae in Israel

Schwaber et al. Clin Infect Dis 2011;52:848-855.

Contact precautionsCohorting CRE patients and staffDaily reporting, feedback from MOH

Summary

• MDR-GNRs pose daunting challenges– Poor evidence base to guide us

• Prevention should focus on:– Reducing emergence

• Antimicrobial stewardship

– Limiting transmission• Hand hygiene, contact precautions• Environmental disinfection

– Preventing infection among carriers• Horizontal measures

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