Prevention of Multiple-Drug Resistant Gram Negative Rod (MDR-GNR) Infections

Daniel J. Diekema, MD, D(ABMM) Professor and Director Division of Infectious Diseases University 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

80 70 60 50 40 30 20 10 0 E. coli Enterobacter P. aeruginosa Klebsiella Acinetobacter

Resistance to 3 or more major classes used to treat.

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

Acinetobacter: Impact of MDR

30 25 30 25 20

Crude mortality

20

15 10 5 0

15 10 5 0

MDR-Acineto

Acineto Crude mortality LOS

Uninfected

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

LOS

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.

MDRO Prevention Approaches

1. Preventing emergence under antimicrobial pressure

2. Preventing transmission
Antimicrobial Stewardship Hand Hygiene Environmental disinfection Contact precautions* Decolonization* Cohorting* SSI, BSI, VAP, UTI prevention 3. Preventing infection among those colonized *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 MDRGNR 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 MDRAcineto 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 nonoutbreak 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

Anatomic site
Groin area

Acineto E. coli
73 71

KPN
100

All
84

Perirectal
Other skin sites Groin + perirectal

29
<30 82

80
<14 100

67
<50 100

50
<28 95

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

Detecting KPC-producing Enterobacteriaceae in LTACH patients

Anatomic site Back/antecubital fossa Oropharyngeal Urine Axillary Inguinal Rectal Rectal + inguinal Sensitivity (%) 25 42 53 75 79 88 100
Thurlow, et al. Infect Cont Hosp Epidemiol 2013;34:56-61.

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

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

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

Hazards of the prior room occupant

Independent Risk Factors MDR PSA (N=82) Prior occupant Surgery Prior Pip Tazo Acinetobacter (N=57) Prior occupant Mech ventilation ESBL-producer (N=50) Tracheostomy Sedation 2.6 (1.1-6.5) 6.6 (1.1-40) 0.049 0.041 4.2 (2-9) 9.3 (1.1-83) <0.001 0.0045 2.3 (1.2-4.3) 1.9 (1.1-3.6) 1.2 (1.1-1.3) 0.01 0.02 0.04 OR (95% CI) P-value

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)

60 50

Acinetobacter MRSA

% rooms +

40 30 20 10 0

2X C/D

4X C/D

1X HPV

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
ICU stay CVC Antibiotics Diabetes

OR (95% CI)
7.5 (1.3-42) 5.7 (1.4-23) 3.3 (1.1-9.7) 2.8 (1.1-7.0)

P
0.02 0.02 0.04 0.03

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

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

OFallon 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) Coag-negative staphylococcus Enterococcus spp Staphylococcus aureus Gram negative (all)

63 30 20 12 33

125 72 35 12 40

Two randomized controlled crossover trials (pediatric and adult ICUs) The difference is mostly among the gram-positive organisms (CoNS) Climo et al. N Engl J Med 2013;368:533-42. Milstone et al. Lancet 2013;January 25.

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 rooms
Science 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 response KPC- K. pneumoniae in Israel

Contact precautions Cohorting CRE patients and staff Daily reporting, feedback from MOH

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

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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