Cases in Antimicrobial Stewardship From the Petri Dish to the Bedside: Part 1

Southern California Branch of the American Society for Microbiology 83rd Annual Meeting

Edina Avdic, Pharm.D, MBA, BCPS, AQ-ID

Associate Director, Antimicrobial Stewardship Program

The Johns Hopkins Hospital (JHH)

Trish Simner, PhD, D(ABMM)

Associate Professor of Pathology

Director of Medical Bacteriology & Infectious Disease Sequencing Laboratories

The Johns Hopkins University School of Medicine

Disclosures

Dr. Avdic – No relevant disclosures

Dr. Simner

• Research Contracts:– BD Diagnostics, Hardy Diagnostics, Accelerate Diagnostics, OpGen, Inc., Affinity

Biosensors

• Consulting: – Roche Diagnostics, OpGen, Inc, CosmosID

Objectives

• Describe how to successfully implement rapid diagnostic tests and demonstrate their value to patients

• Discuss how diagnostics stewardship can improve antimicrobial stewardship

Antimicrobial Stewardship

• Antimicrobial Stewardship (AS)– “Coordinated interventions designed to improve and measure the

appropriate use of antibiotic agents by promoting the selection of the optimal antibiotic drug regimen including dosing, duration of therapy, and route of administration”

• Antimicrobial Stewardship Programs (ASP)– Programs dedicated to improving antimicrobial use

Barlam TF, et al. Clin Infect Dis 2016;62:e52-77.

Antimicrobial Stewardship Team at The Johns Hopkins Hospital

Team• 3 Infectious Diseases (ID) physicians

• 3 ID trained pharmacists

Support• Clinical decision support software

• ID fellows, non-ID trained pharmacists

Collaborators • Hospital epidemiology & infection control

• Microbiology laboratory

• Pharmacy

• ID division

Interventions • Antibiotic Guidelines

• Pre-authorization

• Post-prescription review with feedback

• IV to PO conversion

• Dose optimization

• Syndrome interventions

• Rapid diagnostics interventions

• Pharmacy-driven interventions

• Education and research

Antimicrobial Stewardship Perspective?

• In collaboration with Microbiology laboratory we choose what agents to test and how to best report results

• We translate the results of rapid diagnostics tests to frontline clinicians

• We work with microbiology colleagues to construct antibiograms and monitor resistance patterns

Clinical Microbiologist Perspective

• We are an important arm of the antimicrobial stewardship and infection control teams

• Our results affect downstream actions by both

• We work to understand how we can help each other out to achieve our goals– Discuss protocols

– Identify methods we can implement to help with ASP and HEIC strategies and vice versa

Our Approach

• Monthly- Microbiology/ASP/Hospital Epidemiology Infection Control (HEIC) Meetings– Antimicrobial susceptibility testing (AST) updates

– New diagnostics and implementation – Diagnostic stewardship

– Annual review of the antibiogram

– Antimicrobial resistant organisms detection and surveillance

• We are on the phone or e-mailing each other multiple times a day/week

Medical Microbiology

Hospital Epidemiology and Infection

Control

Antimicrobial Stewardship

Our Team

PART 1: Implementing rapid

diagnostics –It comes down to teamwork!

CASE 1: The target game – rapid diagnostics for bloodstream infections

Current Paradigm for BSI Diagnostics

Standard Culture Based Methods Are Slow - TAT: 3 - 4 DaysWrong empiric therapy = 5x higher mortality 1

25-40% of patients receive ineffective empiric therapy 2

Narrowed TreatmentEmpiric Treatment Targeted Treatment

Instrument signals positive. Perform Gram stain and plate to standard media.

Day 0 Day 1 Day 2

Collection of specimen and placement on automated blood culture monitoring instrument

Day 3

Standard AST panel results available• Setup of additional

antimicrobials

Isolation of organism on solid media• MALDI-TOF MS ID• Setup of AST panel

Day 4

Additional AST results

1. Buehler et al. CMR Jan 2016 Vol 29 No , 2. 2006 Crit Care Med 34:1589. 3. Chest 2000:118;146-55

The correct initial choice of antibiotic therapy has been shown to save more lives than any other medical intervention

Many New Tools Being Introduced

• Rapid identification of the most common pathogens

• Some panels target common resistance genesMultiplex sepsis panels, rapid MALDI-TOF MS ID, Rapid Phenotypic AST

Instrument signals positive. Perform Gram stain and plate to standard media.

Day 0 Day 1 Day 2

Collection of specimen and placement on automated blood culture monitoring instrument

Day 3

Standard AST panel results available• Setup of additional

antimicrobials

Isolation of organism on solid media• MALDI-TOF MS ID• Setup of AST panel

Day 4

Additional AST results

Direct from Whole Blood ID

Our Story: Blood Culture Volumes at JHH

5200

5400

5600

5800

6000

6200

6400

6600

6800

Jul-15 Aug-15 Sep-15 Oct-15 Nov-15 Dec-15 Jan-16 Feb-16 Mar-16 Apr-16 May-16 Jun-16

• Total: 75,057/year• Average: 6,250/month• Positivity rate: ~10%• Average #/day: 208/Day• Positive blood cultures/day:

• ~20/day• ~14 gram-

positive/day• ~6 panels/day

• ~6 gram-negative/day

• ~2-3 panels/day

Top 30 List

Ranks Organism Identification Number Percent Ranks Organism Identification Number Percent

1 Staphylococcus species, coagulase negative 1401 18.70% 16 Serratia marcescens 70 0.93%

2 Escherichia coli 888 11.85% 17 Streptococcus group B 59 0.79%

3 Staphylococcus aureus 864 11.53% 18 Enterococcus faecium 50 0.67%

4 Methicillin resistant Staphylococcus aureus 702 9.37% 19 Enterobacter cloacae 50 0.67%

5 Klebsiella pneumoniae 513 6.85% 20 Streptococcus group A 50 0.67%

6 Pseudomonas aeruginosa 301 4.02% 21 Stenotrophomonas maltophilia 50 0.67%

7 Enterococcus faecalis 255 3.40% 22 Candida parapsilosis complex 49 0.65%

8 viridans Streptococcus group 212 2.83% 23 Candida parapsilosis 44 0.59%

9 Vancomycin resistant Enterococcus faecium 142 1.90%24

Klebsiella oxytoca/Raoultellaornithinolytica

41 0.55%

10 Streptococcus anginosus group 115 1.54% 25 Bacteroides fragilis 34 0.45%

11 Candida albicans 108 1.44%26

Acinetobacter baumannii/calcoaceticus complex

33 0.44%

12 Enterobacter cloacae complex 92 1.23% 27 Streptococcus group C/G 33 0.44%

13 Candida glabrata 90 1.20% 28 Micrococcus luteus 31 0.41%

14 Streptococcus pneumoniae 81 1.08%29

Vancomycin resistant Enterococcus faecalis

30 0.40%

15 Proteus mirabilis 80 1.07% 30 I lost #30

15

Rewind to 2012: Pre-MALDI-TOF MS Era

• Verigene BC-GP Test was the first FDA-cleared multiplex syndromic panel for positive blood cultures

• Worked with ASP to implement & educateGram-Positive Blood Culture (BC-GP) Test

Genus

Staphylococcus spp.

Species

Staphylococcus aureusStaphylococcus epidermidisStaphylococcus lugdunensisStreptococcus spp.

Listeria spp.Streptococcus pneumoniae Streptococcus anginosus GroupStreptococcus agalactiae (GBS) Streptococcus pyogenes (GAS)

Resistance

mecA1

vanA2

vanB2 Enterococcus faecalis Enterococcus faecium

Verigene BC-GP at JHH

• Implemented on March 3, 2013

• Performed 24/7 on blood cultures positive for gram-positive cocci

• Results available with 4 hrs. of positive Gram stain

• First positive bottle

• Consistent overall agreement with conventional results since go-live of 97%

Organism # isolates

Pos.Agreement (%)

Neg. Agreement (%)

MSSA 15 100 100

MRSA 19 100 100

S. epidermidis 8 100 100

S. epidermidis 20mecA pos

100 100

S. lugdunensis 10 100 100

Staphylococcus spp. 12 100 98.3

E. faecium 12 100 98.7

E. faecalis 14 100 99.4

S. pyogenes 10 100 100

S. agalactiae 10 100 100

S. pneumoniae 10 100 100

S. anginosus 11 100 99.4

Streptococcus spp. 15 100 100

Verigene BC-GP Results Reporting

• A negative report will read as follows:– Nucleic Acid Microarray Test negative for:

Staphylococcus species

Streptococcus speciesEnterococcus faecalisEnterococcus faecium Listeria species

• Example of a positive report:– Identified as Staphylococcus aureus, methicillin resistant, by the Nucleic Acid

Microarray Test.

What About Rapid ID of Gram-Negatives?

Organism

Luminex -Verigene BC-GN BiofireFilmArray BCID

GenMark ePlex Accelerate PhenoTest BC

T2 BioSystems –T2 Bacteria

E. coli Yes Yes Yes Yes Yes

Klebsiella pneumoniae Yes Yes Yes Yes, genus level only

Yes

Pseudomonas aeruginosa Yes Yes Yes Yes Yes

Enterobacter cloacae complex Yes, genus level only Yes Yes Yes, genus level only

No

Proteus mirabilis Yes, genus level only Yes, genus level only

Yes Yes No

Serratia marcescens Yes Yes Yes Yes No

Stenotrophomonas maltophilia No No Yes No No

Klebsiella oxytoca Yes Yes Yes Yes, genus only No

Bacteroides fragilis No No Yes No No

Acinetobacter baumannii Yes, genus level only Yes Yes Yes No

Enterobacterales:10-15% extended-spectrum cephalosporin resistance0-8% carbapenem resistance

mecA, vanA/B, blaCTX-M,blaKPC, blaNDM, blaVIM, blaIMP, blaOXA

mecA, vanA/B, blaKPC

mecA/C, vanA/B, blaCTX-

M, blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-23/OXA-48-like

Phenotypic AST Panel

None

To Report OR Not To Report, the Absence of AMR markers…

Negative for AMR Markers Positive for blaKPC

What About Pan Assay Results?

• Allow you to detect a sub-population that may or may not be detected on Gram stain

• How do you convey this result to the team?

• Do you use it more as a tool to guide workup in the lab?

Optimize Patient Treatment with Improved Patient Outcomes

Potential Clinical Impact

AST results–MIC results+/- ID – S/I/R interpretations

Rapid ID within 5 hrs

Rapid ID and AMR genes within 1-3 hrs

~8 hours

Instrument signals positive. Perform Gram stain and plate to standard media.

Day 0 Day 1 Day 2

Collection of specimen and placement on automated blood culture monitoring instrument

Day 3

Standard AST panel results available• Setup of additional

antimicrobials

Isolation of organism on solid media• MALDI-TOF MS ID• Setup of AST panel

Day 4

Additional AST results

Control N = 114

PNA-FISHN = 106

P-value

Time to appropriate therapy, h 21.8 21.2 0.93

Time to optimal therapy, h 32.5 29.0 0.61

In-hospital mortality, n (%) 16 (14.0) 16 (15.1) 0.82

Infection-related LOS, days 9.2 9.3 0.99

• RCT evaluating the impact of PNA-FISH on clinical outcomes of gram-positive cocci in chains in the bloodstream

– PNA-FISH identified E. faecalis, other Enterococcus spp. and Streptococcus spp.

• 2 arms: control vs. PNA-FISH plus notification by laboratory technician who had script

Cosgrove SE, et al. Diagn Microbiol Infect Dis 2016; 86:86-92.

Lesson Learned: RDTs without AS Interventions are Inadequate

Implementation of Verigene BC-GP

Education1. Newsletter with guidelines for interpretation

2. Education sessions for clinical pharmacists

Intervention8:00-17:00 Monday-Friday

• ID pharmacist and clinical pharmacists made interventions

• Evenings and weekends• Pharmacy resident on-call

made interventions if necessary

• 7-months

Follow up7-months

Hopkins Treatment Algorithm for Verigene BC-GP

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Organism Preferred empiric therapy (% susceptible in blood at JHH)

Alternative empiric therapy if PCN allergic

MSSA Oxacillin (100%)Non-severe PCN allergy: CefazolinSevere PCN allergy: Vancomycin1

MRSA Vancomycin (100%) Daptomycin

Coagulase-negative staphylococci Single positive cultures are often a contaminant; no treatment recommended. See page XX of the JHH Antibiotic Guidelines for information and indications for treatment. Call the microbiology lab for more information and further work up if infection suspected (5-6510).

S. lugdunensis Vancomycin (100%)2 Oxacillin (89%) or Daptomycin

E. faecalis Ampicillin (99%) Vancomycin (89%)1

E. faecium (VRE) Linezolid (93%)3 Daptomycin (96.5%)

E. faecium (not VRE) Vancomycin (100%)3 Linezolid

Streptococcus spp.Non-oncology patient: Ceftriaxone4

Oncology patient: Vancomycin4Severe PCN allergy: Vancomycin1

S. anginosus Penicillin G (100%)Non-severe PCN allergy: CeftriaxoneSevere PCN allergy: Vancomycin1

S. pyogenes (group A strep) Penicillin G (100%)Non-severe PCN allergy: CefazolinSevere PCN allergy: Vancomycin1

S. agalactiae (group B strep) Penicillin G (100%)Non-severe PCN allergy: CefazolinSevere PCN allergy: Vancomycin1

S. pneumoniae (not meningitis) Ceftriaxone (94%)4 Severe PCN allergy: Vancomycin1

S. pneumoniae (meningitis) Ceftriaxone + Vancomycin Severe PCN allergy: Chloramphenicol + Vancomycin1

Listeria spp. Ampicillin (100%) Trimethoprim/sulfamethoxazole

Demonstrating Benefits to the Patients

Avdic E, et al. J Antimicrob Chemother 2017;72(11):3191-3198.

We did not observe decrease in length of hospital stay or mortality

Control N=140

InterventionN=160

Post-intervention N=140

P-value

CoNS, Contaminant, n (%) 71 (51) 107 (67) 89 (64) 0.01

Time to discontinuation of therapy: contaminants, median (IQR), hours

18.2 (0-47) 11.7 (0-47) 0* (0-31) 0.86

Infection-related LOS: contaminants,median, IQR, days

7 (3-20) 7 (4-15) 5 (3-15) 0.64

CoNS-Coagulase-negative staphylococci *Difference between post-intervention vs. control (p=0.009) and intervention (p=0.03) was statistically significant

Avdic E, et al. J Antimicrob Chemother 2017;72(11):3191-3198.

Demonstrating Benefits to the Patients

Rapid Diagnostics Integrated into the Standard of Care

Avdic E, et al. J Antimicrob Chemother 2017;72(11):3191-3198.

Case 1: Take Home Points

• ASP and Microbiology laboratory should work closely to select the best test and develop an implementation process

• Real-time AS interventions are necessary during the initial months of implementation of RDTs with clear guidance on antimicrobial selection

• Evaluate and document impact on patient outcomes and reassess need for interventions and re-education

• Demonstrating benefits to patients makes it easier to convince administration to be more receptive to newer RDTs

• Successful implementation standard of practice sustainable benefits to the patients

CASE 2: It doesn’t need to be an expensive molecular test

Presented with a Clinical Need…

• 40-50% of S. aureus encountered at our institution is methicillin-resistant S. aureus (MRSA)

• Has led to empiric treatment of S. aureus infections with vancomycin– Waiting an additional day after ID to de-escalate therapy if MSSA

– Prevents discharge

• Antimicrobial Stewardship wanted a method to rapidly detect MSSA earlier – mecA PCR

Trienski et al, Am J Health-Syst Pharm, 2013.

What about Phenotypic Methods? Penicillin-Binding Protein 2a (PBP2a)

• Rapid phenotypic method to detect the altered PBP2a encoded by mecA from cultured S. aureus isolates– PBP2a SA Culture Colony Test

(Abbott Diagnostics)

• Lateral flow assay

• S. aureus (no induction)

– PBP2a Latex agglutination assay (Thermo Fisher)

• S. aureus (no induction) or CoNS (induction required) 32

Other Scenarios Where the PBP2a Comes in Handy

33

1. Small-colony variant S. aureus

2. Other staphylococci with oxacillin MICs 0.5-2 µg/ml

CLSI, M100-S29.

Huse et al , JCM, 2018. Nacacche et al, JCM, 2019.

Genotype to Phenotype Discordant

Blood culture flags positive

Day 0 Day 1 Day 2

Collection and incubation of the blood culture bottles

Day 3

Growth and confirmation of S. aureus

AST results

Molecular Panel: mecA & Staphylococcus aureus detected by NAT

Oxacillin MIC: ≤0.5 µg/mlSusceptible

What Do You Do When Genotype and Phenotype Don’t Agree?

M100-S29, CLSI, 2019 – Table H1

Laboratory Implications

• Costs: PCR vs Rapid Phenotypic Assay– PBP2a assay was cost-effective

• Workflow: How and when to perform?– Easily incorporated into the techs daily workflow

– All sources (except urine and blood)

– Batch twice daily

– Perform on new S. aureus isolates (repeat after 30 days)

• Resources: Is additional staff required? Instrumentation?

PBP2a Reporting

38

Isolation of your organism on solid media • MALDI-TOF MS ID• Set up of AST panels

Day 0 Day 1 Day 2

Collection and plating of specimen in the lab

Day 3

Standard AST panel results available• Setup of additional

antimicrobials

Additional AST results

Identification of S. aureus • Same day MSSA vs

MRSA call

Optimize Patient Treatment with Potential for Earlier Discharge

Clinical Implications: A success story

Trienski et al, Am J Health-Syst Pharm, 2013.

Implementation of PBP2a assay

• 2nd rapid diagnostics tests at our hospital

• Focus on S. aureus tissue and respiratory cultures

• Intervention: usual practice

• Education:

– Guidelines for interpretation

– Clinical pharmacists were educated on the new test

Demonstrating Benefits to the Patients

BaselineN=119

InterventionN=70

P-value

Patients reaching optimal therapy, n (%) 94 (79) 63 (90) NRTime to optimal therapy (hours), median (IQR)

Respiratory (n=49)Skin or skin structure infections (n=108)

0 (0-64.2)1.7 (0-59)0 (0-70.8)

0 (0.24.7)0 (0-55)0 (0-6.6)

0.020.520.02

Patients reaching antibiotic de-escalation therapy, n (%) 98 (82) 65 (93) NRTime to de-escalation (hours), median (IQR)

Respiratory (n=51)Skin or skin structure infections (n=112)

13.9 (0-71.7)49.2 (0-85.5)9.7 (0-65.6)

0.4 (0-42.9)41.7 (0-64.6)

0 (0-26.5)

0.090.390.05

Length of hospital stay (days), median (IQR) 6 (3-12) 6 (4-14) 0.60

• We elected to stop routinely performing PBP2a assay on the respiratory cultures based on these results

Shulder S, et al. IDWeek Poster 2017.

Case 2: Take Home Points

• Expensive molecular tests are not always the answer– PBP2a assay can be easily incorporated into the lab workflow and can

come in handy for multiple uses in the lab

• Real-time RDT focused AS interventions may not be necessary for simple RDTs at hospital with well established ASP and previous interventions related to RDTs.

• When RDTs are not utilized to optimize therapy, their role should be re-considered by APS and Microbiology laboratory – E.g. right patient population, routine use vs. per-request

CASE 3: One step or two?

Background

• Clostridioides difficile colonization is common in hospitalized patients

• Hospitalized patients frequently have diarrhea

• C. difficile NAAT detects presence of C. diff toxin gene– positive test does not necessarily indicate toxin production or CDI

• Frequent testing – without clinically significant diarrhea

– with clear alternate explanation (e.g. laxative, enteral feeds, chemotherapy)

Slide: Courtesy of Clare Rock

The Clinical Need: C. diff Patient Level Consequences

• Treatment of C. diff colonization results in…

– Administration of unnecessary antibiotics

– Added cost• Unnecessary hospital stay

• Increased health care costs

– Potential disruption of the patient’s intestinal flora, a risk factor for subsequent C. diff disease

Slide: Courtesy of Clare Rock

The Clinical Need: C. diff Facility Level Consequences

• Since 2013, CMS has designated C. diff a hospital-acquired condition

• Health care facility-onset C. difficile infection: requirement to report to CDC National Healthcare Safety Network

• Rates are part of the CMS Hospital Inpatient Quality Reporting (IQR) program

• Data is available on HospitalCompare.com, easily accessed by patients.

• LabID events: does not incorporate chart review– Influenced by test characteristics and ordering behaviors

Slide: Courtesy of Clare Rock

CCNA

GDH 2-stepPCR

EPIC project

Slide: Courtesy of Karen Carroll

What Can Laboratories Do to Improve Test Utilization?

• Computerized Clinical Decision Support (CCDS) for C difficile testing utilization at Johns Hopkins

• Criteria for inappropriate C difficile testing

- Laxative administration within 48 hours

- Previous negative C difficile testing within 7 days

- Previous positive C difficile testing within 14 days

• Best practice alerts (BPA)

- The first BPA - “soft stop”

- The second BPA - “hard stop”

• Safety monitoring

- Retrospective chart review for 3 months post CCDS activation at each hospital47

Slide: Courtesy of Karen Carroll

The first alert screen upon ordering (“Soft Stop”)

Slide: Courtesy of Karen Carroll

The second alert screen upon signing (“Hard Stop”)

Slide: Courtesy of Karen Carroll

Test approval

• A test code for “Approved Microbiology Test C” is obtained by calling microbiology lab.

Yes, you may go ahead and order this C. diff test. Please enter order APPROVED MICROBIOLOGY TEST C (LAB99901) into Epic and order the test this way. You will be asked for a passcode; the passcode is ######. Thank you.

Slide: Courtesy of Karen Carroll

Impact of BPA C. difficile Intervention on the Patient Outcomes

Antibiotic Use for CDI Treatment

• Decrease in oral vancomycin use in the first quarter after BPA activation (incidence risk ratio, 0.69 [95% CI, 0.48–0.99])

Mizusawa M, et al. Clin Infect Dis 2019; [Epub ahead of print]

Ordering Frequency

Safety Outcomes when Testing was Not Pursued

N=102Diarrhea resolved with discontinuation of laxatives 22Alternative cause for symptoms found 21Duplicate order 19Symptoms resolved 14Indeterminate reason for test, patient discharged 12C. difficile negative at a later time during admission 6C. difficile positive at a later time during admission 3C. difficile invalid test at a later time during admission 1Death (unrelated to C. difficile) 3C. difficile positive post discharge/future admission 1

Mizusawa M, et al. Clin Infect Dis 2019; [Epub ahead of print]

Effectiveness of Soft Stopvs. Hard Stop Alert

Slide: Courtesy of Clare Rock

Slide: Courtesy of Clare Rock

BPA initiative started

Slide: Courtesy of Clare Rock

Case 3: Take Home Points

• The right clinical diagnostic for C. difficile will vary by institution

• Use of CCDS to create a BPA can decrease inappropriate C. difficile testing

• Diagnostic stewardship (appropriate testing) improves antimicrobial stewardship

– Decrease disruption to gut microbiota of colonized patients

• It is cost-effective

– Cost to patient, insurance, improves hospital reputation and reimbursement rates

Questions ?

Thank you!