Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
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
25
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!