Enhance Antibiotic Stewardship Efforts
4. Post-implementation tabulation and performance assessment:
a. What will be tabulated once the technology is in place to make sure it is working correctly, and who will monitor it?
i. Time to add, de-escalate to an effective antibiotic or discontinue an antibiotic, or add an antiviral?
ii. Before patient discharge, do cultures need to be obtained and results assessed?
iii. LOS, morbidity, mortality, readmission, cost savings per patient?
iv. How will feedback be presented to the medical staff and to the laboratory and stew-ardship team on performance?
v. How to adjust the process if goals are not what are expected?
Essentially, the greater the effort and thought put into the process of test implementation, reporting, and goals prior to the “go-live” date, the more likely will be the result in optimizing the overall benefits of the test system.
The Rapid Diagnostic Test Menu An astounding array of rapid advanced technolo-gies has emerged for the diagnosis of infectious disease in the midst of other traditional simpler but rapid and informative tests that are still clinically important. The Gram stain and rapid antigen tests used in the appropriate context are such traditional examples that continue to provide both clinically
relevant information and the ability to tailor ther-apy within minutes. The technologies presented in Tables 12.1 and 12.2 are more recent develop-ments. They include a range of pathogens, toxins, and resistance markers that vary in laboratory complexity and cost, and in turnaround time (TAT) to report a result, as well as assays that rely on initial bacterial growth or colony development, and those that are direct sample detection methods. Specifics on the technological components, the targets they identify, and the clinical outcome benefits are referred to in several publications and reviews that are ref-erenced (Wolk and Dunne, 2011; Bauer et al., 2014; Kothari et al., 2014). In addition, diagnostic company websites often provide excellent videos of their technology unique diagnostic features and details of peer-reviewed publications. Examples of emerging less well-known technologies include GeneWEAVE’s Smarticles molecular diagnostics technology (details available at: https://vimeo.
com/126622853) and Accelerate Diagnostic’s in vitro diagnostics (details available at: http://acceler-atediagnostics.com/), both which address rapid susceptibility and antibiotic resistance, as well as BacterioScan’s rapid urinary tract infection (UTI) identification, which also addresses antibiotic resist-ance (details available at: http://www.bacterioscan.
com).
While most of new and rapid tests involve added costs to the microbiology laboratory, many have shown clinical benefits and cost savings for the healthcare system that justify support for the addi-tional laboratory expenditure.
Sepsis
The success of rapid diagnostics and antibiotic stewardship efforts have been most commonly reported in the diagnosis and management of sep-sis, with benefits identified as the appropriate ini-tiation or de-escalation of antibiotics, and decreases in LOS and hospital costs, as well as morbidity and mortality.
The majority of these technologies involve not direct detection from the patient’s blood, but growth from a positive blood culture, which subse-quently yields enough organisms to perform a Gram stain and then specific rapid testing from the broth or from a single colony from a culture plate on the following day. Thus, an initial Gram stain interpretation helps to guide what test platform or multiplex test follows. The Protein Nucleic Acid
New Diagnostics to Enhance Antibiotic Stewardship Efforts127
Table 12.1. Microbiology techniques for rapid detection of pathogens associated with sepsis.
Specimen
source Technology Name (and manufacturer) Target(s)
Technical Published
PBP2a Culture Colony Test
(Alere™)
Penicillin binding protein 2a (detects MRSAa)
No equipment Rapid identification of
MRSA from colony
Sensitivity of test varies in published literature
No studies to date
Protein Nucleic Acid Fluorescent in situ hybridization (PNA FISH®)
Quick FISH™
PNA FISH™
Traffic Light PNA FISH™
Xpress FISH™
with Texas red filter already in most labs
Multiplex PCR Verigene® Gram Negative Blood Culture Test (BC-GN)c (Nanosphere)
8 Gram-negative organisms 6 resistance markers
Fully automated Broad array of targets TAT 2.5 h
Multiple steps Equipment costly
No studies to date
Verigene®
Gram-Positive Blood Culture Test (BC-GP)d (Nanosphere)
12 Gram-positive organisms 3 resistance markers
Fully automated Broad array of targets TAT 2.5 h
Multiple steps, Equipment costly
Yes
BioFire FilmArray® Blood Culture Identification Broad panel with
potential to
128 K.C. Chapin and A.M. Bobenchik
Specimen
source Technology Name (and manufacturer) Target(s)
Technical Published
antibi-otic stewardship outcomes
Benefits Limitations
Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)
MALDI biotyper MS (Bruker Corp) Vitek MS (bioMérieux)
From colony growth: bacteria, yeast, molds, mycobacteria
Identification 15 min Low reagent costs Colony from any
specimen type
Occupies large space Costly equipment US FDAe-cleared
database limitations
Yes (additional positive studies in syndromes other than sepsis) Direct
detection from blood drawn sample
RT (real-time)-PCR LightCycler® SeptiFast (Roche Molecular Systems)
10 Gram-negative organisms 8 Gram-positive organisms 5 Candida spp.
Aspergillus fumigatus
Broad array, including Aspergillus
Not approved in US Yes
PCR with sequencing SepsiTest™ (Molzym) Bacteria and fungi Broad array Not approved in US Time consuming
Yes Nanoparticle-based
PCR
T2 Candida (T2Biosystems®)
5 Candida spp. Fully automated, Direct from blood High NPVf
Costly equipment No studies to date
aMRSA/SA, methicillin resistant Staphylococcus aureus/S. aureus; bTAT, turnaround time; cBC-GN, Gram-negative blood culture; dBC-GP, Gram-positive blood culture; eFood and Drug Administration; fNPV, negative predictive value.
Table 12.1. Continued.
(PNA) Fluorescent in situ hybridization (FISH) assays require only a fluorescent microscope, and are very specific, and so they allow almost any lab to intro-duce this technology. When PNA is performed in conjunction with antibiotic stewardship in place, positive outcomes are common. Similarly, while there is an initial outlay of equipment to perform the BioFire Blood Culture Identification (BCID) assay, which detects 24 of the most common Gram-negative (GN), Gram-positive (GP), and yeast tar-gets, the extensive menu makes the performance of the Gram stain potentially unnecessary. Coupling the Sepsityper™ extraction kit along with Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF MS) allows for the direct detection of a number of different organisms, including aer-obes, anaeraer-obes, and yeast from positive blood cul-tures (Schieffer et al., 2014). This then opens up significant flexibility for ease of testing in many lab settings. Assays for the direct or rapid detection of pathogens in blood and/or of susceptibilities are becoming more common, but the data are still unclear and/or contradictory on the clinical perfor-mance and outcome benefits as far as stewardship practices are concerned, and further assessment is needed. Details of these technologies are presented in Table 12.1.
Rapid testing for infections other than sepsis Hospital-acquired infections
Hospital-acquired infections (HAIs, also known as
“healthcare-acquired infections”) are a considera-ble burden to healthcare systems and have signifi-cant implications for reimbursement. Thus, with the goal of decreased HAI transmission, rapid and sensitive tests, along with targeted antibiotic treat-ment and isolation precautions, are major patient safety and quality measurement goals for hospitals (CDC, 2000).
The most commonly used rapid test for HAIs is a PCR for C. difficile toxins, with the requirement to address appropriate treatment, infection control precautions, and bed placement. The PCR technol-ogies are all statistically equivalent, but differ on the equipment needed, their TATs, and their ability to perform random, small batch, or large batch testing (see Table 12.2). While there is sparse litera-ture on antibiotic stewardship practices per se, there is a significant body of data showing that a concerted HAI team approach among infection
control, microbiology, nursing, pharmacy, and admin-istration can result in decreased transmission, mor-bidity, and mortality (Mermel et al., 2013).
Active, point prevalence or targeted high-risk screening for MRSA/SA in presurgical patients and for MRSA in medical patients is a more controver-sial issue, and has shown varied results for decreased HAI transmission (Hacek et al., 2009; Peterson and Diekema, 2010). However, for many sites, especially the presurgical screening for MRSA/SA in high-risk groups, the identification of carriers, with directed treatment, has commonly resulted in a subsequent decrease in transmission rates, postsurgical infec-tions, and decreased overall costs (Kim et al., 2010).
For laboratories, it is necessary to clarify whether the increased sensitivity of a molecular assay, faster TAT than culture, and automation versus traditional and/or chromogenic media justify the fourfold increase in cost/test (Peterson and Diekema, 2010).
Syndromic panels
Another growing area of rapid testing and one with emerging possibilities for antibiotic stewardship is the use of multiplex PCR assays for syndromic conditions (see Table 12.2).
respiratory diseases Acute respiratory illness is the most common reason that patients come into the healthcare system, and many of them leave with an antibiotic when they have a viral etiology (Chan et al., 2011). Thus, the potential to de-escalate anti-biotics in cases when a viral etiology is diagnosed, or to correctly use antiviral medication depending on whether influenza is detected or not, justify a concerted effort for antibiotic stewardship to address (Jennings et al., 2009; Byington et al., 2012;
McCulloh et al., 2014). Data is beginning to present as to the value of the respiratory viral panel as well as the rapid PCR influenza tests in addressing these changes in use of anti-infectives and infection con-trol issues for admitted patients. In addition, several other antivirals (other than for influenza) are in development, and with the specific identification of a respiratory virus possible, targeted therapy as we currently use for bacterial infections may be possible.
Table 12.2 presents details of both influenza A and B assays, as well as of the respiratory multiplex assays. The available panels of these assays differ in the presence of several bacterial targets in some, whereas others include only viral targets. In addi-tion, the recent arrival of a rapid TB (tuberculosis)
130 K.C. Chapin and A.M. Bobenchik
Table 12.2. Microbiology techniques for rapid detection of pathogens associated with conditions other than sepsis.
Syndrome Meningitis Cerebral spinal
fluid (CSF)
SinglePlex PCR
Xpert EV (Cepheid)
Enterovirus (EV) Ability to discontinue
Simplexa™ HSV-1 & 2 (Focus Diagnostics)
HSV-1 and HIV-2 (herpes simplex virus types 1 and 2)
Rapid
22 Bacterial, viral, and fungal targets
Comprehensive syndromic panel TAT 1 h
Equipment cost, single test per instrument
Alere™ i Influenza A and B test
(Alere™)
Influenza A and B Waived point of care test (POCT) TAT 15 min
No subtyping, clinical performance not as good as other PCR assays
No studies to date
Biplex PCR Xpert Flu (Cepheid) sensitivity of Flu A detection
Yes
Triplex PCR Prodesse Pro Flu+
Prodesse ProFast+
(Hologic)
Influenza A and B RSVa 2 major viruses in pediatric settings TAT 1 h
Initial data 2nd generation test with improved detection for Influenza A/B
No studies to date
Simplexa™ FluA/B RSV Influenza A and B, TAT 2 h Small batch testing No studies
New Diagnostics to Enhance Antibiotic Stewardship Efforts131 Continued
17 Viruses (including Influenza A eSensor® Respiratory
Viral Panel (RVP) (GenMark)
14 Viruses (including Influenza A subtypes)
Test up to 24 samples at a time TAT 6h
No studies to date Verigene® Respiratory
Virus plus test (RV+) (Nanosphere)
Influenza A and B, RSV
No studies to date xTAG® Respiratory Viral
Panel (RVP) (Luminex)
10 Viruses (including Influenza A
Stool SinglePlex
PCR
Multiple manufacturers Performance parameters
not statistically significantly different between manufacturers
tcdB and/ or tcdA toxin gene
Aids in patient isolation TAT 1–2.5 h
May detect carriers, limit testing to appropriate
Multiplex BD Max™ Enteric Panel (BD Biosciences)
22 Bacterial, virus, parasite, and toxin targets
Equipment costs, one test per instrument
No studies to date
132 K.C. Chapin and A.M. Bobenchik
xTAG® Gastrointestinal Pathogen Panel (GPP) (Luminex)
15 Bacterial, virus, parasite, and toxin targets
Increased sensitivity and detection of additional pathogens compared with culture TAT 6 h
Equipment costs, labor intensive, batch testing
Yes
Verigene® Enteric Pathogens (EP) (Nanosphere)
9 Bacterial, virus, and toxin targets
Increased sensitivity and detection of additional pathogens compared with culture TAT 3 h
Equipment costs, labor intensive, batch testing
No studies to date
Mycobacterium tuberculosis respiratory disease
Respiratory specimens
PCR Xpert MTB/RIF
(Cepheid)
M. tuberculosis and rifampin resistance mutations
Both smear positive and negative specimens, allows removal from isolation in suspected cases of TB after 2 negative tests TAT 1 h
Equipment costs Yes
aRespiratory syncytial virus.
Table 12.2. Continued.
Syndrome
Specimen
source Technology
Name (and
manufacturer) Target(s)
Technical benefits
Technical limitations
Published antibiotic stewardship/
outcomes
PCR test (Xpert® MTB/RIF) has allowed more timely identification, treatment, and isolation proto-cols, importantly with a high enough negative predic-tive value to be able to remove patients from isolation and provide cost savings to the hospital (Lippincott et al., 2014).
acutegastroenteritis Currently, there are multi-ple US Food and Drug Administration (FDA)-cleared multiplex assays for the detection of stool pathogens, with more in development. Every panel has a slightly different menu of pathogens, with all containing the major reportable or culturable path-ogens of significance to public health—Salmonella spp., Shigella spp., Campylobacter spp., and shiga toxins sxt-1 and sxt-2. Because it is not uncommon for adults to be prescribed metronidazole and/or cip-rofloxacin empirically, a specific diagnosis would certainly limit antibiotic use, and in some studies, direct treatment to the pathogen actually identified.
In both adults and pediatric patients, what has been shown to date in most studies is that providers can-not accurately diagnose gastrointestinal (GI) patho-gens readily based on symptoms alone, and secondary to overlapping clinical presentations, and that a significant increase in the number of patho-gens detected is found with multiplex testing (Dunbar et al., 2013; Buss et al., 2014; Stockmann et al., 2015). There is a great deal to learn about these assays as far as the interpretation of results goes, as it has not been possible to identify many of these pathogens previously with routine methods.
However, because the diagnosis in the laboratory will be more streamlined compared with culture and other techniques, laboratories will probably imple-ment this technology, and there are likely to be infection control and stewardship benefits down-stream from diagnosing specific infections rapidly (Buss et al., 2014; Goldenberg et al., 2015).
meningitis/encephalitis Currently, there is only one multiplex PCR diagnostic in this group. The BioFire Meningitis/Encephalitis Panel has now been cleared by the FDA and the results are in press. No outcome studies have yet been published.
In contrast, Enterovirus (EV) PCR has been used successfully to de-escalate antibiotics in EV positive patients as well as reduce LOS in febrile infants, and has clear value as a single-plex test because it is the most common meningitis etiology in pediatrics (Dewan et al., 2010).
Deficiencies in Current Rapid Assays While rapid diagnostics has been a great step for-ward in infectious disease diagnosis and antibiotic stewardship efforts, these assays present some diag-nostic and overall healthcare issues. With the molec-ular multiplex assays that have multiple targets, including resistance markers, the debate is whether the target detected is actually representative of disease or colonization and/or if resistance will be expressed.
This is of greatest concern for the detection of C.
difficile toxin, for antibiotic resistance targets for the purpose of treatment, and for the interpretation of multiple targets in a single sample with multiplex assays, where it is not uncommon to find 10–20%
of specimens with more than one pathogen. Thus, for the general provider, interpretation and treatment become more complicated, and education on and the reporting of results from the laboratory of a critical nature (Baron et al., 2013). Importantly, laboratory personnel and those treating the infections cannot presume to know all of the correct answers at this stage. As these assays become more common, it will be exciting to watch the growing understanding of the pathology of diseases and identify how better guidance on treatment can be established. For molec-ular assays in general, there is the obvious potential advantages of a more sensitive and specific result, and a faster TAT, but the cost benefit for some of that performance will have to be carefully weighed to justify the increased costs overall in the healthcare picture.
For simpler routine technologies, such as MALDI-TOF, the issue is a rapid identification, but with no susceptibility data. This can be addressed in part by using “predictive” reporting from an institution’s antibiogram, or by perform-ing direct susceptibility testperform-ing from positive broth cultures, but currently the lack of susceptibility data inhibits antibiotic stewardship from provid-ing clear guidance. New diagnostics in develop-ment direct from clinical samples could potentially address some of the deficiencies seen here. These include unique systems that rely on a component of phenotypic analysis, along with genomic com-ponents, to address the problem of nucleic acid alone “detected” by a molecular assay. The pro-cess occurs in a sped-up fashion of 1–4 h, which is acceptable for clinical care, along with sophisti-cated algorithms to determine identification and susceptibility.
Point-of-care Testing (POCT)
Waived POCT devices exist for molecular based rapid influenza A/B testing and other tests are in development (Table 12.2). This testing potentially brings the era of molecular diagnostics literally to the bedside, and directed antibiotics/antivirals even more rapidly available to the patient with a test that may be better than the current technology. As the assay menu expands, so will the ability to have these instruments become handheld devices with direct connectivity to the EMR. It would not be surprising if these test systems became more commonplace to support timely antibiotic stewardship goals. The cost–benefit compared with rapid response labs, the potential oversight and comparison with other much less expensive methods will have to be assessed per analyte so as not to make them cost prohibitive for the patient and the healthcare system.
Partnering of Diagnostic Companies with Pharmaceuticals
Not surprisingly, diagnostics companies are partner-ing with pharmaceutical companies to expand the development of rapid resistance detection tests.
Given the issue of worldwide resistance issues, this seems to be a logical pursuit and one that will likely enhance development on both the anti-infective and diagnostic side, as well as addressing problems from a different viewpoint as to identifying what is criti-cally needed and how to get it done in a more effec-tive manner.
Evidence-based Care Process Models Evidence-based care process models (EB-CPMs) are now becoming more commonly implemented within a healthcare system with the ultimate goal of qual-ity improvement for patients. Both diagnostic test-ing and clear antibiotic stewardship processes are key to the success of these models. For example, in one large pediatric system assessing febrile infants that appear well, the EB-CPM included a broader menu of diagnostic testing to start with, including rapid Enterovirus testing and respiratory viral panel testing, as well as clear antibiotic empiric choices and duration. While initial diagnostic testing costs were increased, the benefits were statistically signifi-cant for numerous other quality measures, including
earlier discharge without antibiotics in patients diag-nosed with a viral pathogen, no missed meningitis cases, no readmissions for screening and brief inter-vention (SBI), patients more likely to receive only the antibiotics recommended, overall cost savings realized in decreased LOS, and reductions in antibi-otic prescribing and ancillary testing not recommend by the EB-CPM. With the advent of the EMR, these process models are even easier to implement and will become a standard of care with rapid diagnos-tic testing and antibiodiagnos-tic stewardship as the main components (Byington et al., 2012).
Conclusions
Increased diagnostic capabilities for rapid detection of infectious disease pathogens, toxins, and resistance
Increased diagnostic capabilities for rapid detection of infectious disease pathogens, toxins, and resistance