1 Evanston Northwestern Healthcare Research Institute, Evanston Northwestern Healthcare, Division of Microbiology, Department of Pathology and Laboratory Medicine, Northwestern University, Evanston, IL, USA; 2 Pharma Research Centre, Bayer AG, Wuppertal, Germany
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Abstract |
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Keywords: molecular diagnostics, infectious disease diagnosis, antibiotic prescribing, empirical therapy
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Introduction |
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Antimicrobial agent overuse |
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Guidelines have been produced for managing resistance by improving antibiotic prescribing,5,6 and pharmacodynamic concepts have been developed to maximize therapeutic response, prevent emergence of resistance and minimize adverse events.7 However, most interventions to date have been vague and eventually arrive at the concept of using antibiotics wisely to solve the problem.8 Apart from the general concepts of appropriate use there are more precise and predictive tools available to identify patient- and institution-specific variables that may place an individual patient at risk and which may foster resistance development. Based on either antimicrobial surveillance systems or individual susceptibility testing, computer-based modelling methods have recently been developed to identify profiles of either institutions facing resistance problems or an individual patient infected with a resistant strain,9 or to assist infection monitoring and treatment at the bedside.10 Importantly, all this effort has led to little practical implementation or improved drug use by most of the prescribing physicians.
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Advent of improved diagnostics |
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Perhaps the first molecular test that was successful in reducing antibiotic use because a specific diagnosis of viral aetiology could be rapidly made was the application of PCR to the detection of enteroviral meningoencephalitis.16 In 2003, several reports appeared assessing the impact of early detection of infectious agents,17,18 determination of specific antimicrobial agent resistance1820 and the positive impact of rapid results on the prescribing of vancomycin.21 The publication of Beekmann et al.17 found that an increased time to detection of bloodstream infection was independently associated with longer hospital stay and higher cost. In a direct application of molecular diagnostics to patient treatment, Hallin et al.18 reported that 25% of patients benefited from early detection of methicillin resistance using PCR on positive blood culture bottles. An important innovation by Lapierre et al.19 was the development and testing of a novel real-time PCR assay for direct detection of fluoroquinolone resistance in staphylococci, finding a 99.8% correlation between PCR results and MIC measurements, and thus demonstrating the potential to increase dramatically the speed of resistance detection using this new technology. Stefanelli et al.,20 in another excellent technological advance, were able to predict diminished penicillin susceptibility for all Neisseria meningitidis tested within a few hours using real-time PCR. We have applied the real-time PCR assay to the direct detection of Staphylococcus aureus and methicillin resistance in positive blood and wound cultures, again showing a dramatic reduction in the time needed to inform physicians of an accurate diagnosis, which resulted in a rapid modification of empirical antibiotic treatment for 33.8% of patients.21
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Promise of molecular testing |
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The newest and most exciting possibility for specific outpatient diagnosis is that based upon amplification technology such as PCR. Rapidity of testing and cost are always key issues. With the advent of real-time PCR we finally have as a reality access to a reliable diagnostic test with same-day results. Our recent experience with the detection of vancomycin-resistant enterococci (VRE) and S. aureus, both tested directly from perianal and nasal swabs, respectively, and having better recovery than culture, demonstrates that these tests can be sufficiently sensitive for clinical diagnostic requirements.23,24 The cost of this testing also now approximates to that of conventional culture-based processing. Thus, we are on the threshold of microbiology diagnostics that, when carried to its expected conclusion, can provide sufficient information to permit specific application or avoidance of antimicrobial chemotherapy. The newer applications of molecular diagnostics known as gene chip and microarray and nanoparticle technology offer the potential to solve many remaining impediments to rapid detection of important infectious agents in health care. Since these technologies do not require organism viability, and thus avoid any adverse effect of longer specimen transport, they can be successfully applied to both the in- and outpatient settings. Also, the resulting test rapidity theoretically will provide relevant information within a few hours, which would limit any necessary empirical treatment to one or two doses. Several companies currently possess the technical expertise and laboratory research infrastructure to bring a useful diagnostic testing approach to the clinical trial stage very shortly. One example is the new technology company Nanosphere, Inc. (Northbrook, IL, USA), which is developing gold nanoparticle technology to detect molecular DNA, RNA and protein biomarker targets using automated instrumentation, without the need for prior amplification.25 This testing could detect likely pathogens responsible for important clinical scenarios, such as respiratory disease symptom complexes, implicating the key bacterial, viral or atypical microbial pathogens responsible. Simplified automation opens the potential for testing to be done near the patient at a peripheral site. If the testing were widely applied, it could be done at a very manageable cost and would have a significant impact on lowering unnecessary antibiotic prescribing.
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Regulatory challenges |
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Conclusions |
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Footnotes |
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References |
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