T h e R o l e o f th e M i c ro b i o l o g y L a b o r a t o r y i n A n t i m i c ro b i a l S t e w a rd s h i p Pro g r a m s Edina Avdic,
PharmD, MBA
a,
*, Karen C. Carroll,
MD
b
KEYWORDS Antimicrobial stewardship Microbiology laboratory Rapid diagnostics Antibiogram Procalcitonin KEY POINTS Rapid diagnostic technologies can decrease the time to identification of microrganisms and resistance genes, potentially leading to reduced time to optimal therapy and improved clinical outcomes. The benefits of rapid diagnostic techniques are enhanced when coupled with antimicrobial stewardship interventions. Procalcitonin-guided therapy can reduce antimicrobial consumption by decreasing the initiation of antimicrobial therapy and decreasing the duration of therapy. Clinical microbiology laboratories should work closely with antimicrobial stewardship programs to compile institution-specific antibiograms. Antibiograms are frequently used by stewardship programs to make formulary decisions, develop guidelines for empiric therapy, and monitor local resistance rates over time.
INTRODUCTION
The major goals of antimicrobial stewardship programs (ASPs) are to optimize antimicrobial dosing, duration, and route of administration for each patient while minimizing adverse drug events and the emergence of antimicrobial resistance.1,2 The clinical microbiology laboratory plays an essential role in these stewardship activities. Microbiology laboratories perform timely identification of microbial pathogens and antimicrobial susceptibility testing, and ensure proper attention to the preanalytical components of testing, which are often unrecognized tasks that can impact quality results. For example, most laboratories provide guidelines for appropriate specimen
Disclosures: Dr E. Avdic does not have disclosures. Dr K.C. Carroll has received research funding from BioFire Diagnostics, Inc, Nanosphere, Inc, and Curetis, Inc. She is on the scientific advisory boards of Quidel Biosciences, Inc and NanoMR, Inc. a Department of Pharmacy, The Johns Hopkins Hospital, Osler 425, 600 North Wolfe Street, Baltimore, MD 21287, USA; b Departments of Pathology and Medicine, The Johns Hopkins University School of Medicine, Meyer B1-193, 600 North Wolfe Street, Baltimore, MD 21287, USA * Corresponding author. E-mail address: [email protected] Infect Dis Clin N Am 28 (2014) 215–235 http://dx.doi.org/10.1016/j.idc.2014.01.002 0891-5520/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
id.theclinics.com
216
Avdic & Carroll
collection, enforce rejection criteria for specimens inappropriately submitted, and have established procedures for limiting the work-up of contaminants (eg, blood cultures), all of which could impact antimicrobial use.3 The preanalytical component of testing is not discussed in detail in this article and additional information can be found in the comprehensive document published by Baron and colleagues.3 The last decade has seen an unprecedented plethora of rapid, broad-based, and sensitive diagnostic tests that provide simultaneous organism identification and resistance marker detection. Optimal use of such assays provides tools that increase the effectiveness of antimicrobial stewardship (AS) activities and promote program growth.4,5 Simultaneously laboratorians and ASP have pursued incorporating biomarkers, such as procalcitonin (PTC), into algorithms to differentiate infectious causes of fever or sepsis from noninfectious inflammatory conditions. Finally, clinical microbiology laboratories are essential for the surveillance of antimicrobial-resistant organisms and for organizing and communicating resistance trends in written form, such as antibiograms. This article focuses primarily on the rapid tests that have been shown to optimize stewardship activities and reviews the evidence for using PTC. In addition, the value and limitations of antibiograms are also discussed in some detail. RAPID DIAGNOSTIC TESTS FOR ORGANISM IDENTIFICATION
The past two decades have seen an explosion in the development of rapid diagnostic methods including nonamplified probe technologies, proteomics, and nucleic acid amplification methods combined with microarray technologies. A brief overview of several assays can be found in Table 1. These tests can significantly reduce time to organism identification compared with standard methods and lead to faster susceptibility results by detecting resistance markers. Moreover, when incorporated with AS interventions they can reduce the time to effective antimicrobial therapy, overall antimicrobial use, lengths of hospital stay, and hospital costs.5–17 Summary of the studies evaluating rapid diagnostics can be found in Table 2. Peptide Nucleic Acid–Fluorescence In Situ Hybridization
Peptide nucleic acid–fluorescence in situ hybridization (PNA-FISH) technology (AdvanDx, Inc, Woburn, MA) uses fluorescein-labeled probes that target pathogenspecific 16SrRNA of bacteria or 26SrRNA of yeast. After a blood culture bottle signals growth and a Gram stain is performed, the appropriate PNA-FISH probe can rapidly (20 minutes–1.5 hours) identify several important pathogens.5 PNA-FISH probes have been cleared by the US Food and Drug Administration (FDA) for the following pathogens: Staphylococcus aureus and Coagulase-negative staphylococci; Enterococcus faecalis and other Enterococcus spp; Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa; Candida albicans, C parapsilosis, C tropicalis, C glabrata, and C krusei. At this time, PNA-FISH tests do not detect resistance markers. However, a probe that detects the mecA gene has been evaluated in a recent clinical trial for FDA approval and will likely be available sometime in 2014 (Karen Carroll, personal communication, 2013). Forrest and colleagues6 conducted one of the first studies to evaluate the impact of a PNA FISH assay on patient outcomes. The investigators used an S aureus singleprobe on positive blood cultures from non–intensive care unit (ICU) patients in conjunction with AS interventions. PNA-FISH results were reported in real time to an ASP that then assessed the need for vancomycin therapy and restricted its release. Investigators reported a significant decrease in median length of hospital stay from
Table 1 Features of select rapid diagnostic assays currently used in clinical practice Manufacturer
Specimen
Organisms
PNA FISH
AdvanDx, Inc, Woburn, MA
Blood
Staphylococcus aureus/coagulase-negative staphylococci, mecAa Enterococcus faecalis/other Enterococcus spp, Escherichia coli/Klebsiella pneumoniae/Pseudomonas aeruginosa, Candida albicans/C parapsilosis/C tropicalis/ C glabrata/C krusei
qPCR
BD GeneOhm, Inc, Sparks, MD; Cepheid, Sunnyvale, CA; Roche Molecular Systems, Inc, Indianapolis, IN
Blood, S aureus wounds
MALDI-TOF MS Bruker Daltonics, Inc, All body Billerica, MA; bioMerieux, sites Inc, Durham, NC
Large number of organisms including bacteria and yeast
Time FDA Required (h) Cleared 0.3–1.5
Yesa
Yes
None
0.2
No
2.5
Yes
2.5
Yes
1
Yes
Nanosphere, Inc, Northbrook, IL
Blood
mecA, vanA, Staphylococcus spp, S aureus, S epidermidis, vanB S lugdunensis; Streptococcus spp, S pneumoniae, S pyogenes, S agalactiae, S anginosus group; E faecalis, E faecium, Listeria spp
Nucleic acid microarray BC-GN
Nanosphere, Inc, Northbrook, IL
Blood
Escherichia coli/Shigella spp, Klebsiella pneumonia, Klebsiella oxytoca, P aeruginosa, Serratia marcescens, Acinetobacter spp, Proteus spp, Citrobacter spp, Enterobacter spp
Blood
Enterococcus spp, Listeria monocytogenes, mecA, vanA, Staphylococcus spp, S aureus, Streptococcus spp, vanB, KPC S agalactiae, S pyogenes, S pneumoniae, A baumannii, Haemophilus influenzae, Neisseria meningitides, P aeruginosa, E cloacae complex, E coli, K oxytoca, K pneumoniae, S marcescens, Proteus spp, Enterobacteriaceae spp, C albicans, C parapsilosis, C tropicalis, C glabrata, C krusei
KPC, NDM, CTX-M, VIM, IMP, OXA
Microbiology Laboratory and ASP
mecA/SCCmec 1–2
Nucleic acid microarray BC-GP
BioFire, Inc, Multiplex Salt Lake City, UT nucleic acid amplification test
a
Resistance Markers
Technology
Probe for mecA gene has been evaluated in a recent clinical trial, but not yet FDA approved.
217
218
Avdic & Carroll
Table 2 Studies evaluating rapid diagnostic tests for organism identification Organisms/ Antimicrobial Resistance Targets
Impact on the Antimicrobial AS-I Therapy
Technology
Reference
Study Design
PNA-FISH
Forrest et al,6 2006
Staphylococcus aureus Yes Retrospective, costsingle probe effective analysis comparing PNAFISH result combined with AS interventions to historical control in patients with CoNS bacteremia Single probe Candida Yes Before and after albicans design evaluating potential costsavings of PNA-FISH result combined with AS in patients with candidemia Enterococcus faecalis/ Yes Quasiexperimental other Enterococcus study, pre and post spp PNA-FISH implementation with AS interventions in patients with GPCPC bacteremia
Forrest et al,7 2006
Forrest et al,8 2008
Other Outcomes
Notes
Significant reduction Nonsignificant trend in median length of toward less stay (4 vs 6; P
PharmD, MBA
a,
*, Karen C. Carroll,
MD
b
KEYWORDS Antimicrobial stewardship Microbiology laboratory Rapid diagnostics Antibiogram Procalcitonin KEY POINTS Rapid diagnostic technologies can decrease the time to identification of microrganisms and resistance genes, potentially leading to reduced time to optimal therapy and improved clinical outcomes. The benefits of rapid diagnostic techniques are enhanced when coupled with antimicrobial stewardship interventions. Procalcitonin-guided therapy can reduce antimicrobial consumption by decreasing the initiation of antimicrobial therapy and decreasing the duration of therapy. Clinical microbiology laboratories should work closely with antimicrobial stewardship programs to compile institution-specific antibiograms. Antibiograms are frequently used by stewardship programs to make formulary decisions, develop guidelines for empiric therapy, and monitor local resistance rates over time.
INTRODUCTION
The major goals of antimicrobial stewardship programs (ASPs) are to optimize antimicrobial dosing, duration, and route of administration for each patient while minimizing adverse drug events and the emergence of antimicrobial resistance.1,2 The clinical microbiology laboratory plays an essential role in these stewardship activities. Microbiology laboratories perform timely identification of microbial pathogens and antimicrobial susceptibility testing, and ensure proper attention to the preanalytical components of testing, which are often unrecognized tasks that can impact quality results. For example, most laboratories provide guidelines for appropriate specimen
Disclosures: Dr E. Avdic does not have disclosures. Dr K.C. Carroll has received research funding from BioFire Diagnostics, Inc, Nanosphere, Inc, and Curetis, Inc. She is on the scientific advisory boards of Quidel Biosciences, Inc and NanoMR, Inc. a Department of Pharmacy, The Johns Hopkins Hospital, Osler 425, 600 North Wolfe Street, Baltimore, MD 21287, USA; b Departments of Pathology and Medicine, The Johns Hopkins University School of Medicine, Meyer B1-193, 600 North Wolfe Street, Baltimore, MD 21287, USA * Corresponding author. E-mail address: [email protected] Infect Dis Clin N Am 28 (2014) 215–235 http://dx.doi.org/10.1016/j.idc.2014.01.002 0891-5520/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
id.theclinics.com
216
Avdic & Carroll
collection, enforce rejection criteria for specimens inappropriately submitted, and have established procedures for limiting the work-up of contaminants (eg, blood cultures), all of which could impact antimicrobial use.3 The preanalytical component of testing is not discussed in detail in this article and additional information can be found in the comprehensive document published by Baron and colleagues.3 The last decade has seen an unprecedented plethora of rapid, broad-based, and sensitive diagnostic tests that provide simultaneous organism identification and resistance marker detection. Optimal use of such assays provides tools that increase the effectiveness of antimicrobial stewardship (AS) activities and promote program growth.4,5 Simultaneously laboratorians and ASP have pursued incorporating biomarkers, such as procalcitonin (PTC), into algorithms to differentiate infectious causes of fever or sepsis from noninfectious inflammatory conditions. Finally, clinical microbiology laboratories are essential for the surveillance of antimicrobial-resistant organisms and for organizing and communicating resistance trends in written form, such as antibiograms. This article focuses primarily on the rapid tests that have been shown to optimize stewardship activities and reviews the evidence for using PTC. In addition, the value and limitations of antibiograms are also discussed in some detail. RAPID DIAGNOSTIC TESTS FOR ORGANISM IDENTIFICATION
The past two decades have seen an explosion in the development of rapid diagnostic methods including nonamplified probe technologies, proteomics, and nucleic acid amplification methods combined with microarray technologies. A brief overview of several assays can be found in Table 1. These tests can significantly reduce time to organism identification compared with standard methods and lead to faster susceptibility results by detecting resistance markers. Moreover, when incorporated with AS interventions they can reduce the time to effective antimicrobial therapy, overall antimicrobial use, lengths of hospital stay, and hospital costs.5–17 Summary of the studies evaluating rapid diagnostics can be found in Table 2. Peptide Nucleic Acid–Fluorescence In Situ Hybridization
Peptide nucleic acid–fluorescence in situ hybridization (PNA-FISH) technology (AdvanDx, Inc, Woburn, MA) uses fluorescein-labeled probes that target pathogenspecific 16SrRNA of bacteria or 26SrRNA of yeast. After a blood culture bottle signals growth and a Gram stain is performed, the appropriate PNA-FISH probe can rapidly (20 minutes–1.5 hours) identify several important pathogens.5 PNA-FISH probes have been cleared by the US Food and Drug Administration (FDA) for the following pathogens: Staphylococcus aureus and Coagulase-negative staphylococci; Enterococcus faecalis and other Enterococcus spp; Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa; Candida albicans, C parapsilosis, C tropicalis, C glabrata, and C krusei. At this time, PNA-FISH tests do not detect resistance markers. However, a probe that detects the mecA gene has been evaluated in a recent clinical trial for FDA approval and will likely be available sometime in 2014 (Karen Carroll, personal communication, 2013). Forrest and colleagues6 conducted one of the first studies to evaluate the impact of a PNA FISH assay on patient outcomes. The investigators used an S aureus singleprobe on positive blood cultures from non–intensive care unit (ICU) patients in conjunction with AS interventions. PNA-FISH results were reported in real time to an ASP that then assessed the need for vancomycin therapy and restricted its release. Investigators reported a significant decrease in median length of hospital stay from
Table 1 Features of select rapid diagnostic assays currently used in clinical practice Manufacturer
Specimen
Organisms
PNA FISH
AdvanDx, Inc, Woburn, MA
Blood
Staphylococcus aureus/coagulase-negative staphylococci, mecAa Enterococcus faecalis/other Enterococcus spp, Escherichia coli/Klebsiella pneumoniae/Pseudomonas aeruginosa, Candida albicans/C parapsilosis/C tropicalis/ C glabrata/C krusei
qPCR
BD GeneOhm, Inc, Sparks, MD; Cepheid, Sunnyvale, CA; Roche Molecular Systems, Inc, Indianapolis, IN
Blood, S aureus wounds
MALDI-TOF MS Bruker Daltonics, Inc, All body Billerica, MA; bioMerieux, sites Inc, Durham, NC
Large number of organisms including bacteria and yeast
Time FDA Required (h) Cleared 0.3–1.5
Yesa
Yes
None
0.2
No
2.5
Yes
2.5
Yes
1
Yes
Nanosphere, Inc, Northbrook, IL
Blood
mecA, vanA, Staphylococcus spp, S aureus, S epidermidis, vanB S lugdunensis; Streptococcus spp, S pneumoniae, S pyogenes, S agalactiae, S anginosus group; E faecalis, E faecium, Listeria spp
Nucleic acid microarray BC-GN
Nanosphere, Inc, Northbrook, IL
Blood
Escherichia coli/Shigella spp, Klebsiella pneumonia, Klebsiella oxytoca, P aeruginosa, Serratia marcescens, Acinetobacter spp, Proteus spp, Citrobacter spp, Enterobacter spp
Blood
Enterococcus spp, Listeria monocytogenes, mecA, vanA, Staphylococcus spp, S aureus, Streptococcus spp, vanB, KPC S agalactiae, S pyogenes, S pneumoniae, A baumannii, Haemophilus influenzae, Neisseria meningitides, P aeruginosa, E cloacae complex, E coli, K oxytoca, K pneumoniae, S marcescens, Proteus spp, Enterobacteriaceae spp, C albicans, C parapsilosis, C tropicalis, C glabrata, C krusei
KPC, NDM, CTX-M, VIM, IMP, OXA
Microbiology Laboratory and ASP
mecA/SCCmec 1–2
Nucleic acid microarray BC-GP
BioFire, Inc, Multiplex Salt Lake City, UT nucleic acid amplification test
a
Resistance Markers
Technology
Probe for mecA gene has been evaluated in a recent clinical trial, but not yet FDA approved.
217
218
Avdic & Carroll
Table 2 Studies evaluating rapid diagnostic tests for organism identification Organisms/ Antimicrobial Resistance Targets
Impact on the Antimicrobial AS-I Therapy
Technology
Reference
Study Design
PNA-FISH
Forrest et al,6 2006
Staphylococcus aureus Yes Retrospective, costsingle probe effective analysis comparing PNAFISH result combined with AS interventions to historical control in patients with CoNS bacteremia Single probe Candida Yes Before and after albicans design evaluating potential costsavings of PNA-FISH result combined with AS in patients with candidemia Enterococcus faecalis/ Yes Quasiexperimental other Enterococcus study, pre and post spp PNA-FISH implementation with AS interventions in patients with GPCPC bacteremia
Forrest et al,7 2006
Forrest et al,8 2008
Other Outcomes
Notes
Significant reduction Nonsignificant trend in median length of toward less stay (4 vs 6; P
