MICHELLE PEAHOTA, PHARMD, BCPS Incorporating Rapid Diagnostic Microbiology Testing into Antimicrobial Stewardship

M I C H E L L E P E A H O TA , P H A R M D , B C P S

Incorporating Rapid Diagnostic Microbiology Testing into

Antimicrobial Stewardship

Objectives

1. Describe recent advancements in microbiology rapid diagnostic testing

2. Review current literature describing the impact of rapid diagnostic testing on antimicrobial stewardship and patient outcomes

3. Evaluate the incorporation of rapid diagnostics into an antimicrobial stewardship program to identify positive blood cultures

Case 1

HPI: MJ is a 68 YO M end stage renal disease (ESRD) on hemodialysis (HD) (MWF) presents to ER from HD clinic after he was noted to have chills, rigors, and a fever of 102.1. In the ER he is lethargic and febrile. The ER sent 2 sets of blood cultures.

PMH: ESRD on HD (HD catheter), Diabetes, Hypertension

Allergy: penicillin (GI upset)

Medications: Insulin glargine, metoprolol, zolpidem prn, docusate, senna

Social history: Denies IVDA, no tobacco, no alcohol

The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters. Which empiric antibiotic should be started?

The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA negative. What (if any) changes should be made to MJ’s antibiotic

regimen?

Case 1

Antimicrobial Stewardship Program (ASP)

ID Physician Clinical Pharmacist Microbiology

Information Systems Specialist

Epidemiologist

Early Antibiotic Administration

Septic shock Acute organ dysfunction secondary to documented or

suspected infection Major health care issue

Effective antimicrobial administration Impact on mortality Timing is important Selection is important

Early Antibiotic Administration

Kumar et al., Crit Care Med. 2006.

Antibiotic Selection

Drug allergies

Patient history

Antimicrobial

ExposureComorbidities

Local susceptibility

patterns

Initial selection should be broad enough to cover all likely pathogens

Empiric therapy should be tailored to local susceptibility patterns

De-escalate when causative pathogen has been identified

Microbiology

Alert of positive culture

Organism identification (ID)

Antimicrobial susceptibility

Traditional Microbiologic Methods for ID

Gram

stain

Plate

culture

Incubate

Perform

biochemical

tests/culture

based-techniq

ue

Obtain ID

Set up antimicrobial susceptibilities Antimicrobial Susceptibility

Initiate empiric therapy De-escalate or escalate therapy

Definitive therapy

Time Required to Deliver Routine Bacterial Culture Results

Goff DA, et al. Pharmacother. 2012.

Rapid Molecular Identification Methods

Rapid methods that can deliver results minutes to a few short hours

Several commercially available tests

Enable timely antimicrobial optimization

“Game changer”

Polymerase chain reaction (PCR)

Multiplex PCR

Nanoparticle Probe Technology (Nucleic Acid Extraction and PCR Amplification)

Peptide Nucleic Acid Fluorescent In Situ Hybridization

Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF)

Rapid Molecular Identification Methods

MALDI-TOF

Matrix-assisted laser desorbtion/ionization time-of-flight mass spectrometry

Ability to analyze thousands of samples per day

Multiple sources: blood, respiratory, urine, wound

Identifies bacteria based on unique protein sequences Ionization and disintegration of target molecule Mass/charge ratio analyzed Mass spectrum provides a profile of the organism compared to those of well-

characterized organism in a library

Process ~1 hour

MALDI-TOF

Able to reduce time to organism ID by 24-36 hoursCan not detect resistance mechanisms Limitation in organism ID at species level

Streptococci, Shigella, Propionibacterim

MALDI-TOF


PNA-FISH

One of the first commercially available rapid diagnostic tests for blood

Synthetic oligonucleotide fluorescence-labeled probes Hybridization to species-specific ribosomal RNA Fluorescence is detected using a fluorescence microscope

Organism detection S. aureus, coagulase-negative staphylococci (CoNS) Enterococci Gram negative rods (Pseudomonas, Klebsiella, E.coli) Candida (C. albicans, glabrata, C. parapsilosis, C. krusei, C.

tropicalis) mecA probe (MRSA)


Testing time 20 minutes - 2 hours

Robust clinical experience

Limited targets

Limited detection of resistance mechanisms


Polymerase Chain Reaction

PCR

Uses fluorescent probe with 2 primers

Amplify target DNA

Amplification and detection in 1 process

Multiplex PCR >1 set of primers Simultaneous detection of multiple organism and resistance patterns

Polymerase Chain Reaction (PCR)

https://www.youtube.com/watch?v=0HCWmD7Mv8U

Nucleic Acid Amplification

Utilizes a fluorescently labeled piece of target DNA Use of 2 primers Amplify a piece of target DNA

Amplification and detectionNanosphere VerigeneTM

BioFire FilmArrayTM Blood culture identification (BCID) panel

FilmArray BCID tests for 24 organims Gram positive Gram negative Yeast

BioFire FilmArrayTM

Micro Organism

Gram positive Enterococcus, L. monocytogenes, Staphylococcus, S. aureus, Streptococcus, S. agalactiae, S. pyogenes, S. pneumoniae

Gram Negative Acinetobacter baumanni, Haemophilus influenzae, Nisseria meningitidis, Pseudomonas aeruginosa, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus, Serratia marcescens

Yeast Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis

Antibiotic resistance genes-mecA – methicillin resistance-vanA/B- vancomycin resistance -KPC- carbapenem resistance

Obtain organism ID and some resistance genes

Ability to escalate and de-escalate for certain situations Staphylococcus Enterococcus

Only able to escalate therapy for gram negatives

Only able to detect select organisms – still need traditional micro ID

Nucleic Acid Amplification

What next?

Action to results Decreased time to ID Decreased time to detection of select resistance genes Opportunity to improve patient care

Timing

S. aureus

MRSA vs. MSSA mecA gene encodes for methicillin resistance (PBP-2a) Vancomycin for MRSA

Vancomycin less active against MSSA than anti-staph β-lactams Increased failure rates Higher risk of relapse

MSSA bacteremia Drug of choice

Nafcillin or oxacillin Cefazolin

Detection of S. aureus bacteremia with PCR and ASP’s Impact

Clinical and economic outcomes

Xpert MRSA kit (Cepheid) and GeneXpert realtime-PCR platform: MRSA vs. MSSA

Single Center study Compared patients with S. aureus bacteremia Intervention arm:

Microlab notified ID pharmacist and treating physician ID pharmacist paged treating physician and communicated lab results and

recommendations Targeted therapy Antibiotic optimization Infectious Diseases Consult

Bauer, et al. CID 2010.

ResultsMean time to switch to optimal antibiotic

Mean time to switch from empiric vancomycin to β-lactam for MSSA decreased by 1.7 days (P=0.002)

LOS 6.2 days shorter (P=0.07)

Hospital costs decreased $21,387 less per patient (P=0.02)

Detection of S. aureus bacteremia with PCR and ASP’s Impact

Bauer, et al. CID 2010.

Coagulase-Negative Staphylococcus

CoNS

Common pathogen associated with hospital-acquired central line infection

Commonly isolated as a contaminant from blood culture Bacteremia vs. contamination

True bacteremia = treat Contaminant = discontinue antibiotics

Impact of ASP Intervention on CoNS Blood Cultures in Conjunction with Rapid Diagnostics

Analyzed the impact of rapid diagnostics with MALDI–TOF plus ASP intervention

Single center, quasiexperimental study Historical control – CoNS identified by conventional methods Intervention – CoNS blood culture ID’ed vial MALDI in

conjunction with ASP intervention

Nagel JL, et al, J Clin Microbiol. 2014.


Nagel JL, et al, J Clin Microbiol. 2014.

MALDI ID CoNS quicker than traditional methods (83.4 vs 57 h, P=0.001)

Antibiotics No difference in time to effective therapy Decrease in time to optimal therapy (58.7 vs 34.4h, P=0.03)

Similar LOS, ICU stay, recurrent bacteremia and hospital readmission

Intervention group had lower mortality rate (21.7% vs 3.1%, P=0.023)

Decreased duration of inappropriate antibiotic administration with vancomycin and daptomycin (4.4 vs 3 days, P=0.015)


Enterococci

Enterococcal bacteremia is the 4th most common cause of hospital-acquired bacteremia in the US Most common species E. faecium and E. faecalis

Vancomycin resistant enterococci (VRE) Most commonly E. faecium Daptomycin Linezolid

Early appropriate antimicrobial therapy has shown to improve patient outcomes in the ICU

PNA-FISH and Enterococcus

Blood culture with gram positive cocci in chains (GPCC)

PNA-FISH E. faecalis Other enterococci (which include E. faecium) No detection Streptococci

Use information to guide antimicrobial therapy

PNA-FISH for Enterococcal Bacteremia

Quasiexperimental study

Control group E. faecium and E. faecalis

were ID using conventional methods

ASP intervened by clinical factors and final susceptibility

Intervention Group

PNA-FISH ASP intervened at time of

PNA-FISH results

Forrest GN, et al. Antimicrob Agents Chemother. 2008.

PNA-FISH ID E. faecalis 3 days and E. faecium 2.3 days earlier than conventional methods (P<0.001)

Reduction in time to initiating effective therapy (1.3 vs 3.1 days, P<0.001)

Decreased 30 day mortality (26% vs 45%)

PNA-FISH in conjunction with ASP treatment algorithm decreased time to appropriate empiric therapy

Forrest GN, et al. Antimicrob Agents Chemother. 2008.

PNA-FISH and Enterococcus

Integrating Rapid Diagnostics and ASP to Improve Outcomes in Patients with Gram-Negative Bacteremia

Impact of rapid ID (MALDI-TOF) and susceptibility testing coupled with ASP on patients with resistant gram-negative bacteremia

Control group: conventional ID and susceptibility

Intervention group: MALDI ID Simultaneous set up for susceptibility testing Results sent to ASP ASP contacted team to discuss results and provide evidence based

recommendations when appropriate

Perez KK. J Infect. 2014.

MALDI reduced time to ID (40.9±15.1 h to 14.5±12.3 h, P<0.001)

Susceptibility testing (46.7±12.9 h to 29.3±14.7, P<0.001)

Decreased time to optimal antibiotics (80.9±63 h to 23.2 ±19.9 h, P<0.001)

Decreased LOS

Decreased mortality

Decreased hospital costs $26,298 per each bacteremic patient


Integrating Rapid Diagnostics and ASP to Improve Outcomes in Patients with Gram-Negative Bacteremia

Timeline Comparison


Rapid Diagnostic Testing in Conjunction with ASP

Case 1

HPI: MJ is a 68 YO M end stage renal disease (ESRD) on hemodialysis (HD) (MWF) presents to ER from HD clinic after he was noted to have chills, rigors, and a fever of 102.1. In the ER he is lethargic and febrile. The ER sent 2 sets of blood cultures.

PMH: ESRD on HD (HD catheter), Diabetes, Hypertension

Allergy: penicillin (GI upset)

Medications: Insulin glargine, metoprolol, docusate, senna, zolpidem prn

Social history: Denies IVDA, no tobacco, no alcohol

The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters. Which empiric antibiotic should be started?

The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray™. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA gene negative What (if any) changes should be made to MJ’s antibiotic

regimen?

Case 1

The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters.

Which antibiotic is most appropriate to start given the available information?

a) Cefazolin

b) Vancomycin

c) Linezolid

d) Cephalexin

Case 1

The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters.

Which antibiotic is most appropriate to start given the available information?

a) Cefazolin

b) Vancomycin

c) Linezolid

d) Cephalexin

Case 1

Case 1

The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray™. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA gene negative

Which antibiotic is most appropriate for MJ’s infection?

a) Cefazolin

b) Vancomycin

c) Linezolid

d) Cephalexin

e) Daptomycin

Case 1

The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray™. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA gene negative

Which antibiotic is most appropriate for MJ’s infection?

a) Cefazolin

b) Vancomycin

c) Linezolid

d) Cephalexin

e) Daptomycin

Case 2

LT is a 30 YO M with no significant PMH presents to the ER with fevers, SOB, and productive cough.

PMH: depression

Allergies: ciprofloxacin (hives/urticaria)

Social History: denies IVDA, +EtOH, no tobacco

Medications: sertraline

CXR: patchy airspace opacities concerning for pneumonia

The ER sent 2 sets of blood and sputum cultures and started IV azithromycin and ceftriaxone for CAP

The lab performed a gram stain and notifies the ER that 1 blood culture bottle has gram positive cocci in clusters on gram stain

The ER added vancomycin to LT’s antibiotic regimen

Case 2

LT is admitted to the observation unit

LT is clinically stable, SOB and cough resolving

Temp 98.9, HR 65 BMP, BP 132/80

WBC 12

Blood cultures: 1 out of 2 sets growing Coagulase negative Staphylococcus (from anaerobic bottle only), repeat blood cultures are negative

Sputum culture: rejected due to poor sample collection

Case 2

Given the available information, what is the most appropriate action?

a) Continue vancomycin IV for 14 days, goal trough 15-20 mg/L

b) Discontinue vancomycin and narrow to cefazolin for 14 days

c) Discontinue vancomycin and discharge patient on oral course of antibiotics for CAP

d) Discontinue vancomycin and start daptomycin since CoNS is likely vancomycin resistant

Case 2

Given the available information, what is the most appropriate action?

a) Continue vancomycin IV for 14 days, goal trough 15-20

b) Discontinue vancomycin and narrow to cefazolin for 14 days

c) Discontinue vancomycin and discharge patient on oral

course of antibiotics for CAP

d) Discontinue vancomycin and start daptomycin since CoNS is likely vancomycin resistant

Case 2

Thomas Jefferson University Hospital

Large academic medical center 951 acute care beds 45,131 admissions per year Wide range of clinical specialties

Microbiology Lab Services 3 hospital campuses Over 10,000 specimens per month ~4,000 blood specimens per month

Thomas Jefferson University Hospital

Antimicrobial stewardship program Prospective audit with feedback and intervention ICU stewardship rounds Treatment guideline development

Infectious Diseases Subcommittee Members include pharmacists, ID physicians, and

microbiologist Drug policy Guidelines

MALDI-TOF Direct from blood Urine Sputum Tissue

Biofire FilmArray Direct from blood

Rapid Diagnostic Testing at TJUH

Workflow

Result notification

Empiric antimicrobial selection for bacteremia guideline

ASP intervention

Documentation



Lab notifies team of +

gram stain

Lab performs ID on rapid diagnostic

technology

Lab sends ASP ID

results as well as notifies team of ID

ASP reviews results and if appropriate

contacts team to provide

intervention

Follow up and documentatio

n

TJUH Future Directives

Bacteremia bundles

Data collection

Outcomes research

Economic impact evaluation

Conclusion

Timely administration of optimal antimicrobial therapy is essential to improving patient outcomes

Rapid diagnostic testing in conjunction with ASP efforts have demonstrated positive results

New technologies in combination with ASP will likely continue to demonstrate improvements in antimicrobial use and patient care

References

1. Dellit T, Owens R, McGowan J, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. CID. 2007;44:159-77.

2. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006; 34:1589-96.

3. Goff DA, Jankowski C, Tenover FC. Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial stewardship programs. Pharmacother. 2012;32(8):677-87.

4. Bauer KA, West JE, Balada-Llasat JM, et al. An antimicrobial stewardship program’s impact with rapid polymerase chain reaction methicillin-resistant Satphylococcus aureus/S. aureus blood culture test in patients with S. aureus bacteremia. Clin Infect Dis. 2010;51:10174-80.

5. Nagel JL, Huang AM, Kunapuli A, et al. Impact of antimicrobial stewardship intervention on Coagulase-Negative Staphylococcus Blood Cultures in Conjunction with Rapid Diagnostic Testing. J Clin Microbiol. 2014;52(8):2849-54.

6. Forrest GN, Roghmann MC, Toombs LS, et al. Peptide nucleic acid fluorescent in situ hybridiazation for hospital-aquired enterococcal bacteremia: delivering earlier effective antimicrobial therapy. Antimicrob Agents Chemother. 2008; 52:3558-63.

7. Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid pathogen identification and antimicrobial stewardship improves outcomes in patients with antibiotic resistant gram-negative bacteremia.

8. Wong JR, Bauer KA, Mangino JE, et al. Antimicrobials tewardship pharmacist interventions for coagulase-negative staphylococcus positive blood cultures using rapid polymerase chain reaction. Ann Pharmacother. 2012;46:1484-90.

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MICHELLE PEAHOTA, PHARMD, BCPS Incorporating Rapid Diagnostic Microbiology Testing into Antimicrobial Stewardship