MDRO and nMDRO: A Briefing for Clinical and Public Health - - PowerPoint PPT Presentation

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MDRO and nMDRO: A Briefing for Clinical and Public Health Microbiologists

September 19, 2019 Speaker: Janet Hindler Moderator: Paula Snippes-Vignone

Information, tools, and references used in this program reflect the opinion of the presenter and are not recommendations or requirements endorsed by the LA County Department of Public Health or Association of Public Health Laboratories.

♦Discuss the definitions for MDRO and novel MDRO (nMDRO). ♦List MDRO that currently represent the greatest threats to healthcare facilities and the community. ♦Describe laboratory responsibilities for detecting and reporting MDRO.

At the conclusion of this program, you will be able to:

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Check separate reference list provided with this webinar!

https://clsi.org/standards/products/free- resources/access-our-free-resources/

Specimen: Blood Diagnosis: Pyelonephritis

• E. coli

amikacin S ampicillin R cefazolin R ceftriaxone R ciprofloxacin R ertapenem S gentamicin S meropenem S piper-tazo R tobramycin S trimeth-sulfa R

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Infection preventionist wants to know if this is an MDRO…

Is it??

Resistance Concepts and MDRO

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Intrinsic “R”

• Naturally occurring or innate
• r normal “R” that a

bacterium possesses to an antimicrobial agent(s)

• Representative of all or

almost all (>99%) isolates of a genus or species

CLSI M100 29th ed “Intrinsic R Tables” 6

Never report “S” for agent to which the organism has intrinsic “R” ..report “R” or suppress

Intrinsic “R”

• Naturally occurring or innate
• r normal “R” that a

bacterium possesses to an antimicrobial agent(s)

• Representative of all or

almost all (>99%) isolates of a genus or species

Acquired “R”

• A bacterium that was

previously “S” can become “R” as a result of

• Spontaneous gene

mutation and selection

• Acquisition of R genes

from another bacterium (same or different species)

CLSI M100 29th ed “Intrinsic R Tables”

“R” gene on plasmid

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Never report “S” for agent to which the organism has intrinsic “R” ..report “R” or suppress

• Example:

KPC gene from K. pneumoniae to

• E. coli and S. marcescens

Sidjabat et al. 2009. Clin Infect Dis. 49:1736.

Agent

• E. coli

Enterobacter cloacae Pseudomonas aeruginosa Acinetobacter baumannii Stenotrophomonas maltophilia amikacin S S S S R ampicillin S R R R R cefazolin S R R R R cefepime S S S S S ceftriaxone S S R S R ciprofloxacin S S S S S ertapenem S S R R R gentamicin S S S S R meropenem S S S S R pip-tazo S S S S R tobramycin S S S S R trim-sulfa S S R S S

Wild Type (Normal) Profiles

(R = intrinsic Resistance) Must know when and how to detect acquired “R”

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MDRO - Definitions

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What are MDRO?

• No universal

comprehensive definition or single list of MDRO!

• Resistant to one key drug

(e.g., MRSA, VRE)

• Resistant to one or more

drugs from several drug classes

• Harbor specific “R” genes

(e.g., mecA, KPC)

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What are MDRO?

• No universal

comprehensive definition or single list of MDRO!

• Resistant to one key drug

(e.g., MRSA, VRE) OR

• Resistant to one or more

drugs from several drug classes

• Harbor specific “R” genes

(e.g., mecA, KPC)

Why are MDRO a big deal?

• Treatment options limited
• MDRO infections are

associated with increased lengths of stay, costs, and mortality

• Significant challenge for

infection preventionists and public health professionals

• Must minimize spread!

MDROs are important from treatment and infection prevention perspectives!

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2012 Global Effort to Standardize Definitions

♦ MDR – multidrug-R (e.g., “not susceptible” to at least 1 drug in ≥ 3 drug classes) ♦ XDR – extensively drug-R (e.g., “not susceptible” to almost all classes but retains “S” to at least one drug class) ♦ PDR – pandrug-R (e.g., “R” to all drugs available)

Magiorakos et al. 2012. Clin Microbiol & Infection. 18:268-281.

• Definitions apply to “acquired” (vs. “intrinsic”) resistance and to

drugs that might be used to treat an infection caused by the species.

• Limitation – based on testing nearly all available antimicrobial

agents.

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Provides data about healthcare-associated infections (HAIs) including those caused by antibiotic resistant bacteria. [as reported through CDC’s National Health Safety Network (NHSN)] Includes “Phenotype Definitions” of MDR

CDC’s Antibiotic Resistance Patient Safety Atlas

For MDRO definition, should we use “Resistant” or “Not Susceptible” interpretation?

♦ Resistant ♦ Not Susceptible includes: – Resistant – “Intermediate (I)” – “Susceptible Dose Dependent (SDD)”

Organism Group MIC (µg/ml) S I SDD R Enterobacteriaceae - gentamicin ≤4 8

• ≥16

Enterobacteriaceae - cefepime ≤2

• 4-8

≥16

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Definition Antimicrobial Groups “R” to at least 1 drug in at least 3 or 4 of the 6 antimicrobial groups Tobramycin (not Serratia) OR gentamicin Piperacillin-tazobactam Imipenem (not Proteus) OR meropenem Cefotaxime OR ceftriaxone OR ceftazidime Ciprofloxacin Trimeth-sulfamethoxazole

Adapted from: Canadian recommendations for laboratory interpretation

• f MDR GNR; German, GJ et al. 2018. Can Commun Dis Rep. 44:29-34.

MDRO Enterobacteriaceae

Based on drugs commonly tested in clinical labs! ..also have XDRO definition for Enterobacteriaceae

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Definition Antimicrobial Groups “R” to at least 1 drug in all 5 antimicrobial groups Ciprofloxacin Piperacillin-tazobactam Ceftazidime Imipenem OR meropenem Tobramycin

XDRO Pseudomonas aeruginosa Acinetobacter spp.

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Adapted from: Canadian recommendations for laboratory interpretation

• f MDR GNR; German, GJ et al. 2018. Can Commun Dis Rep. 44:29-34.

No MDRO definition…only XDRO definition for P. aeruginosa and Acinetobacter

Practical List MDRO

♦ MRSA (and VISA, VRSA) ♦ VRE ♦ GNR resistant to all drugs on panel ♦ GNR resistant to all drugs on panel except carbapenems ♦ Extended-spectrum cephalosporin-R E. coli, Klebsiella, Proteus mirabilis (ESBL and ampC phenotype) ♦ Carbapenem-R GNR – Enterobacteriaceae (CRE) – P. aeruginosa (CRPA) – Acinetobacter (CRAB) ♦ Candida auris ♦ S. pneumoniae (penicillin-R in LTCF) ♦ Neisseria gonorrhoeae – extended-spectrum cephalosporin, nonsusceptible

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Novel MDRO (nMDRO)

♦ Rare or uncommon to region ♦ Pan-R isolates

– Very rare in USA

Los Angeles County nMDRO ♦ Suspect Pan-R isolates

– “Not susceptible” to all drugs on the clinical lab’s panel

♦ Rare carbapenemases, e.g.

– P. aeruginosa VIM, IMP – K. pneumoniae NDM

♦ Candida auris ♦ VISA / VRSA

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CRPA isolated

Infection Preventionist

Oh my!!

LA Hospital

Public Health Epidemiologist

LA County Public Health Lab VIM + IMP Positive by PCR

Outbreak Investigation:

• PH epidemiologist visited hospital
• Noted excellent infection prevention

practices (enhanced after 1st nMDRO confirmed)

• No additional cases!

CRPA, carbapenem-resistant P. aeruginosa

An nMDRO Story

19 CRPA #2 isolated

Los Angeles County Carbapenemase-Producing Species*

*Isolates submitted from clinical laboratories that were positive for “big 5” carbapenemases 2015-2019 (N=1589)

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Los Angeles County Carbapenemase Distribution*

*Isolates submitted from clinical laboratories that were positive for “big 5” carbapenemases 2015-2019 (N=1589)

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Big 5….. KPC NDM VIM IMP OXA

Pseudomonas aeruginosa VIM + IMP positive

amikacin >32 R aztreonam 8 S cefepime >16 R ceftazidime >16 R ceftolozane- tazobactam >256/4 ciprofloxacin >2 R colistin 2 S gentamicin >8 R meropenem >8 R piper-tazo 32 I tobramycin >8 R

VIM IMP

MIC (µg/ml)

Metallo beta-lactamases

An nMDRO Story

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Why are we concerned about Candida auris?

♦MDRO

– Some resistant to all 3 antifungal classes – Approximately 90% are resistant to fluconazole and 30% to amphotericin B (unpublished data, CDC)

♦Causes outbreaks in healthcare settings

– Colonizes skin and healthcare environments in contrast to other Candida spp. Can be misidentified as Candida haemulonii or

• ther Candida spp.

Google CDC Candida auris – many resources!

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https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html

Clinical cases of Candida auris reported by U.S. states, as of July 31, 2019

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CLSI and Testing/Reporting

• f MDRO

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CLSI is addressing MDRO by…

♦ Providing guidance for:

– Selective reporting (suppression) of antimicrobial agents – Testing / reporting supplemental agents on MDRO – Confirming uncommon results – Detection of resistance mechanisms (e.g., ESBL, carbapenemases), when needed for epidemiology

♦ Reassessing breakpoints to ensure “clinical” resistance and susceptibility are reliably detected ♦ Providing guidance for preparation of cumulative antibiograms (CLSI M39-A4 document)

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What does CLSI say about MDRO?

Section I.D. Selective Reporting1 “Selective reporting should improve the clinical relevance of test reports and help minimize the selection of multiresistant strains by overuse of broad-spectrum agents.”

Always report unexpected resistance!

1 report broad-spectrum agents only when isolate is

resistant to narrower-spectrum agents

CLSI M100 29h ed “Instructions for Use” 27

Table 1A. Suggested Agents to Test/Report

Table 1A Drugs to Test/Report

CLSI M100 29th ed. 28

Specimen: Fluid Diagnosis: Wound Infxn Serratia marcescens

amikacin 2 S ampicillin >32 R cefazolin >32 R ceftriaxone ≤0.5 S ciprofloxacin ≤0.25 S gentamicin 1 S meropenem >4 R piper-tazobactam ≤8/4 S tobramycin 1 S trimeth-sulfa ≤1/19 S MIC (µg/ml)

Dien-Bard et al. 2010. Clin Micro Newsltr. 32:77.

Report Unexpected “R” Final Report

Meropenem NOT reported when other β-lactams are “S” but this is unexpected “R”; REPORT (Isolate produced SME carbapenemase)

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What else does CLSI say about MDRO?

Section I.D. Selective Reporting

. . .

“In addition, each laboratory should develop a protocol to address isolates that are confirmed as resistant to all agents on their routine test panels. This protocol should include options for testing additional agents in-house or sending the isolate to a reference laboratory.” (Also a CAP requirement - MIC.21944)

CLSI M100 29th ed “Instructions for Use” 30

Specimen: Pleural fluid Diagnosis: Emphysema Pseudomonas aeruginosa

amikacin >32 R ceftazidime >32 R ciprofloxacin >4 R gentamicin >16 R meropenem >8 R piper-tazobactam >128/4 R tobramycin >16 R MIC (µg/ml)

Note: SOP should

include steps:

• Other potential useful

agents to test

• How testing will be done

(e.g., in-house or send to reference lab)

• How to communicate

with MD; MD to suggest additional drugs to test, if appropriate

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Potential “Consequences” of Reporting or Missing an MDRO (ie, erroneous AST results)

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Potential Consequences of Reporting Erroneous AST Results

False Susceptible False Resistant Prescribe drug that does not work Prescribe broader spectrum agent (not always more effective) Prolong illness; increase length of hospitalization Prolong illness; increase length of hospitalization Prolong exposure to antimicrobials If MDRO reported, “isolation precautions” might be needed; psychological impact; often difficulties in transfer to LTCF or similar facility Prolong presence of “bug” may increase potential spread to others Potential for “R” development to broader spectrum agent – unavailable for future use Perform additional procedures to evaluate for foci of infection Could lead to labor-intense epidemiological investigation. Increase costs Increase costs 33

Specimen: Blood; Trach Aspirate 1 Diagnosis: Bacteremic pneumonia Enterobacter cloacae

Agent Blood Trach Aspirate

• E. cloacae
• E. cloacae

amikacin S R cefepime S R ciprofloxacin S R gentamicin S R meropenem S R piper-tazo R R tobramycin S R trimeth-sulfa R R

Question: Why might AST results differ?

1 Both specimens collected at same time

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Specimen: Blood; Trach Aspirate Diagnosis: Bacteremic pneumonia Enterobacter cloacae

Agent Blood Trach Aspirate

• E. cloacae

E. cloacae

• S. maltophilia

amikacin S S R cefepime S S R ciprofloxacin S S R gentamicin S S R meropenem S S R piper-tazo R R R tobramycin S S R trimeth-sulfa R R S

Conclusion: Original E. cloacae AST from trach aspirate was mixed.

Following repeat testing

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CLSI M100 29th ed.

Appendix A Confirm Patient’s Results

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How do we confirm unusual or uncommon AST results…may need to do one or more of the following…

♦ Check for transcription errors, contamination, or defective panel, plate, or card. ♦ Check previous reports on the patient to determine if the isolate was encountered and confirmed earlier. ♦ Repeat organism ID and AST with initial method to ensure they reproduce.

Reflected light Transmitted light

Examining purity plate ♦ Confirm organism ID with second method. ♦ Confirm AST with second method …e.g., CLSI reference method (eg, broth or agar dilution, or disk diffusion) or a commercial test. * *in-house or at a referral laboratory

CLSI M100 29th ed. Appendix A. 37

Newer Drugs for MDRO

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Agent (*US FDA approved) KPCs NDM 1 OXA-48

• like 1

Carbapenem- resistant

• P. aeruginosa

Carbapenem- resistant

• A. baumannii
• S. maltophilia

Aztreonam-avibactam Ceftazidime-avibactam* Cefotolozane-tazobactam* Imipenem-relebactam* Meropenem-vaborbactam* Cefiderocol Eravacycline* 2 Fosfomycin (IV) Plazomicin* Polymyxin B* / Colistin* Tigecycline* 2

Adapted from Tamma P & Hsu AJ. 2019. J Ped Infect Dis. 8:251.

What about activity of antimicrobial agents for carbapenem-R GNR?

Intrinsic R or %S <30% %S 30-80% %S >80%

1 metallo-beta-lactamase (MBL); 2 activity of minocycline similar

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What about newer US FDA-approved agents for MRSA and VRE?

Antimicrobial Agent MRSA VR

• E. faecium

Other (all yes) Other (all yes, in vitro) Dalbavancin yes VS E. faecalis

• E. faecium

Daptomycin yes yes, in vitro VS E. faecalis VR E. faecium; VR E. faecalis Delafloxacin yes

• E. faecalis

Eravacycline yes

• E. faecalis; E. faecium

Lefamulin yes, in vitro Linezolid yes yes VR E. faecalis Omadacycline yes

• E. faecalis
• E. faecium

Oritavancin yes VS E. faecalis

• E. faecium

Tedizolid yes

• E. faecalis
• E. faecium

Telavancin yes VS E. faecalis Tigecycline yes yes, in vitro VS E. faecalis VR E. faecium; VR E. faecalis

As noted in FDA Prescribing Information: Yes = shown to be active against most isolates, both in vitro and in clinical infections Yes, in vitro = >90% S; efficacy not confirmed in controlled clinical trials 40

CDC’s AR Laboratory Network

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CDC’s Antibiotic Resistance (AR) Laboratory Network supports nationwide lab capacity to:

• rapidly detect antibiotic

resistance in healthcare, food, and the community

• inform local responses to

prevent spread and protect people

Launched 2015

AR Lab Network is in place in Public Health Labs

• 50 states, 4 cities, Puerto Rico
• 7 Regional Labs

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Clinical and Public Health Laboratories work closely with Infection Preventionists and Public Health Epidemiologists

Enhanced Capacity Through Tiered Testing

P H L

State/local PHL

• Organism identification
• Confirmatory AST
• Phenotypic screening for

carbapenemase production

• Molecular detection of mechanism

Network of participating clinical laboratories

Re g i o n al

Regional lab

• Confirmatory testing: full directory
• Colonization screening
• Targeted surveillance for emerging

AR threats

• Whole genome sequencing

CRE and CRPA Healthcare-associated infections C D C

• Confirmatory

testing

• Whole Genome

Sequencing

• Applied research

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CRE, carbapenem-resistant Enterobacteriaceae CRPA, carbapenem-resistant P. aeruginosa

How is AR Lab Network helping clinical labs now?

♦ Full characterization of CRE/CRPA isolates

– Phenotypic testing for carbapenemase production (e.g. mCIM) – Molecular ID of carbapenemase (e.g. KPC, NDM, VIM, IMP, OXA)

♦ Many labs can or soon will…

– Confirm Candida auris identification – Perform additional AST Capacity varies by state; check with your local Public Health Laboratory

State/local PHL

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♦ Colonization (surveillance) screening during confirmed/suspected outbreaks

– CRE, CRPA – Candida auris

♦ Testing of newer drugs – aztreonam- avibactam (not FDA approved)

– testing for “MDRO” and metallo-beta-lactamase producers (e.g. NDM) All testing results are tied directly to public health response in line with CDC’s Containment Strategy

Regional Lab

How is AR Lab Network helping clinical labs now?

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How many MDRO are there?

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Threat levels:

• Urgent

CRE

• C. difficile

Drug-R GC

• Serious

MDR Acinetobacter + Others

• Concerning

VRSA + Others

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• Lists numbers of infections / deaths
• Update scheduled for Fall 2019

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Resistance Phenotype Percent “R” MRSA 46.4 % VR E. faecalis 6.9 % VR E. faecium 77.3 %

• E. coli MDR

7.5 % Klebsiella MDR 14.2 %

• P. aeruginosa MDR

14.2 % Acinetobacter MDR 54.8 % CRE 3.5 %

AR data from CDC’s Antibiotic Resistance Patient Safety Atlas

Examples from Nationwide Data

Percentage of CRE & CRPA that are Carbapenemase Producing (CP)

Total: 22,674 Total:15,012

2017-2018

Preliminary data; subject to change

Carbapenemase-Producing (CP) Enterobacteriaceae by Genera

CP-CRE Distribution (N=8,145) Percent of CRE that are CP-CRE by Genera (N=8,145)

Preliminary data; subject to change

2017-2018

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Carbapenemase Type by Organism

CP-CR Enterobacteriaceae N=8317 CP-CR P. aeruginosa N=330

2017-2018

52 Preliminary data; subject to change

Antibiograms and “Counting” MDRO in Your Facility

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Routine Cumulative Antibiogram % Susceptible1

Organism N A-S P-T Ceftaz Mero Amk Gent Tob Cip T-S

• A. baumannii

73 51 43 44 58 58 50 54 47 51

1 Calculated from first isolate/pt (CLSI M39-A4)

Organism N Ox Clin Ery T-S Cip Van Dap Lnz

• S. aureus

1648 55 72 53 99 48 100 100 100

♦ # of patients (1st isolate) with MRSA (45% of 1648 = 742) ♦ # of patients (1st isolate) with A. baumannii

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Acinetobacter baumannii

(N=73 patients; 8 had multiple isolates with >1 profile)

Resistance Profile # patients %1 Amk, A-S, Ceftaz, Cip, Mero 24 32.9 A-S, Ceftaz, Cip, Mero 5 6.8 Amk, A-S, Ceftaz, Cip 3 4.1 Ceftaz 4 5.5 Cip 3 4.1 Other (10 profiles) 14 19.3 NO Resistance 28 38.4 Drugs examined (primary choices for A. baumannii): Amk - amikacin A-S – amp-sulbactam Ceftaz - ceftazidime Cip - ciprofloxacin Mero - meropenem

1of 73 patients with A. baumannii

32 patients with MDRO if definition is “R” to at least 1 drug in 3 or more classes

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What else might labs need to better confront MDRO…..?

♦ More data on occurrence of MDRO

– How many MDRO of various types have been encountered?

♦ Information on options for treating MDRO infections

– What agents are useful? – How much “R” is there to newer agents among specific MDRO?

♦ Options for testing newer agents

– Commercial AST systems

• Provide verification protocols

– Referral laboratories

• Commercial laboratories

– Public health laboratories (e.g., AR Lab Network)

♦ Easy way to implement updated breakpoints

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Summary

♦ There is no universally accepted definition or “list” for MDRO. ♦ MDRO present significant challenges for laboratorians, clinicians, infection prevention practitioners and public health professionals. ♦ Laboratorians can assist in confronting MDRO by:

– Following CLSI guidelines for accurate detection of resistance – Utilizing “selective reporting” protocols – Reporting “unexpected” resistance – Structuring laboratory reports to highlight MDRO – Testing agents beyond those on routine panel when MDRO are encountered – Communicating with Antibiotic Stewardship, Infection Preventionists, Public Health etc. about MDRO isolates in timely manner – Maintaining relationship with Public Health to help prevent spread of MDRO – Preparing cumulative antibiograms and other reports as requested to monitor MDRO – Keeping abreast of newer developments related to MDRO!

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…to those listening today and staff at:

• APHL
• Los Angeles County Public Health

Lab and Epidemiology sections

• ARLABnetwork

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jhindler@ucla.edu