Looking beyond the laboratory is not preposterous

In an era when we equip our laboratories with the most up-to-date technologies—such as MALDI-TOF mass spectrometry (MS), rapid multiplex polymerase chain reaction (PCR) techniques, and workflow automation solutions—it is always astonishing to see the imbalance between the resources invested in improving the analytic portion of microbiology testing and the other steps required in the production of a laboratory test result, from the “pre-pre-” to the “post-post-” analytical phases.

The process required to generate a valid laboratory test result consists of several steps. According to the “brain-to-brain turnaround time loop” described by Lundberg in 1981 (1), the process can be further divided into nine steps of which the analysis, per se, is only one; the rest of these steps are considered “extra-analytical” (2). The total testing process (TTP), or total testing cycle, involves a series of activities that begin with the clinical question posed by the ordering physician; this leads to the selection of a test, all the subsequent steps that bring the specimen to the analyzer at the lab, the professional validation, the reporting back to the clinician, the interpretation of the test significance, and the impact of this interpretation on decision making (3).

Before a specimen reaches its analysis phase, several steps are required; these are grouped as the pre-analytical phase. The pre-analytical phase begins with ordering a test, followed by specimen collection, identification, transportation, and preparation. These steps are essential and, from a microbiologist’s perspective, include selecting the proper collection device (swab, container, etc.), performing the collection procedures (to limit contamination, to reach the minimal adequate volume), providing adequate labelling, and transporting the specimen within an acceptable timeframe at the suggested temperature. Finally, they also include the application of rejection criteria and specimen preparation. The post-analytical phase of testing includes all the steps in the overall laboratory process between completion of the analytical phase and the receipt of results by the requesting physician. This phase includes validation, formatting, reporting, and interpretation of the results (2,3).

During the last decade, the analytical step has gone through significant changes in microbiology, allowing for more rapid, accurate results, and the possibility of managing a higher volume of tests. Several studies have shown a direct impact of the implementation of new microbiological technologies on clinical outcomes. Examining 112 consecutive positive blood cultures at a tertiary care centre in Vancouver, Payne et al. showed a mean time to identification of 2.4 hours and 2.9 hours, respectively, when using a rapid multiplex PCR (the BIOFIRE FILMARRAY Blood Culture Identification Panel [bioMérieux, St. Laurent, QC]) and MALDI-TOF MS directly on positive blood culture broth. This represents a decrease of almost 24 hours compared to standardized culture-based identification (4). While they reported 44 antimicrobial modifications following rapid identification and antibiogram, the study was not designed to show an impact on other clinical outcomes (4). This is one of many examples in which new rapid technologies can decrease the turnaround time significantly with the potential for improving the quality of patient care.

Although considerable technological improvements in the quality assessment processes at the analytical stage have reduced the error rate significantly, the same cannot be said for the extra-analytical phases of testing, during which the proportion of errors has been reported to be 4 to 5 times that seen in the analytical phase and with the pre-analytical phase contributing more than half the errors (3,5). These phases are error-prone because they involve important human factors and logistics and can be associated with negative clinical outcomes; for example, urine specimens that have not been refrigerated between collection and analysis have been reported to have a significantly higher risk of contamination rate (16.3% vs. 8.3%, p = 0.02) (6). In recent years, considerable effort has been targeted at improving the extra-analytical phases, exemplified by the inclusion of several accreditation requirements for these specific steps. For instance, ISO 15189:2012, an international standard specifying the quality management system requirements for medical laboratories, covers all three phases of the TTP (7,8). This standard will be implemented in all Québec medical laboratories in the future.

Even by perfecting the extra-analytical phases of testing from a laboratory standpoint, we are still missing critical aspects of the “brain-to-brain loop” such as the following:

1. Are clinicians selecting the appropriate tests to confirm their clinical hypothesis?

2. Are these tests already completed elsewhere in the network by other clinicians?

3. Do the test results trigger appropriate clinical decisions (i.e., do they indicate the need for further complementary tests, or for initiating appropriate treatments and follow-up procedures)?

All these steps refer to two additional analytical steps that are probably as important for the patients: the pre-pre-analytical, or initial part of the pre-analytical phase focused on the test selection; and the post-post-analytical, or final part of the post-analytical phase, mainly the interpretation of results by the clinician (3,9). What is the relevance of a perfectly processed test with rapid turnaround time, impeccable validation, and lightning-fast transmission, if the clinician at the end does not react rapidly and adequately on the result?

A new term has emerged in recent years to highlight the importance of the pre-pre-analytical phase: diagnostic stewardship (DS), or selecting the right test for the right patient at the right time. Does this ring a bell? The motto associated with DS is very similar to the antimicrobial stewardship mantra: the right drug, at the right time and dose, and for the right duration. It involves modifying the process of ordering, performing, and reporting to improve the treatment of infections or other diseases (10). Some examples of targets for DS include the following:

1. Collecting specimens before antimicrobials are started

2. Resisting the urge to request urine cultures in a patient with no urinary-related symptoms (unless another valid reason exists)

3. Limiting the use of swab specimens and the culture of skin flora commensals when better specimens can be collected (aspirates, fluid, or tissue)

4. Ensuring that the volume of blood drawn for blood cultures reaches 20 to 30 mL

5. Providing antimicrobial susceptibility in cascading fashion, by preferentially reporting a group of narrow-spectrum agents

There are several solutions to improve these two overlooked phases. For the pre-pre-analytical phase, integration of alerts in the electronic health record at the moment of ordering to signal to the clinician the presence of duplicate testing has been associated with interesting results (11). The integration of clinical data from several outpatient clinics and hospitals from the same network increases the power of this approach significantly. Frequently, a clinician is not aware of a recent test performed by the patient’s primary care physician and will re-order the same test. The detection and management of these duplicates are probably more efficient at the time of physician order than in the laboratory. The implementation of strategies based on education to diffuse updated collection protocols is central to improve this step. The Choosing Wisely initiative also targets the pre-pre-analytical phase by providing targets and education to prescribers to reduce the ordering of tests with limited added value. For instance, this would mean prescribing only Clostridioides difficile tests, urine cultures, urinalysis, and blood cultures of patients who have symptoms (12).

Several aspects of the post-post-analytical step can be integrated into antimicrobial stewardship (AS) activities. By performing reviews of potential asymptomatic bacteriuria (based on positive urine cultures, negative urinalysis in a patient receiving antibiotics with an absence of symptoms), the AS team ensures a test is interpreted correctly, and inappropriate antimicrobials discontinued. Applying antibiogram results to reduce the use of broad-spectrum antimicrobials, identifying patients with the presence of a pathogen in a normally sterile site without antimicrobials, are other examples found at the post-post analytical stage.

There is a clear overlap between DS and AS objectives, and the risk of confusing or undermining AS with DS has been raised as a critique of DS (13). Also, other experts have suggested viewing quality improvement in infectious disease/microbiology as an integrated process by creating the antimicrobial, infection prevention, and diagnostic (AID) stewardship model (14). We prefer the latter, as it emphasizes the several interactions between the sub-specialties of the practice of infectious disease/microbiology: antimicrobial optimization, better use of laboratory testing, and infection prevention and control strategies.

In the near future, when the optimal goal is to provide the best-integrated surveillance of clinical processes, the stewardship approach should aim to be as inclusive as possible. Instead of only targeting microbiology tests, or targeting antimicrobial use, the future stands in the real-time surveillance of integrated processes, also called syndrome-based antibiotic stewardship. For instance, in a patient with Staphylococcus aureus bacteremia, we should not only optimize the current antimicrobial treatment by an audit and feedback approach (e.g., by narrowing the spectrum if the organism is methicillin-susceptible), or build in protocols to ensure that the appropriate volume of blood is collected. We should also build automated processes to be sure the patient has an echocardiogram, has repeat blood cultures within 48 to 72 hours of the last positive culture, and has a consultation from cardiac surgery should they meet surgical criteria.

This type of syndrome-based approach is the future of effective infection management but will necessitate open-mindedness and adaptation by clinicians. In the long run, this type of strategy can only be successful by engaging an active collaboration with local opinion leaders in non–infection-focused specialties (15), by evaluating the impact on improving these steps on meaningful outcomes through evaluative research projects, and by integrating these types of collaborative approaches within the educational programs of the faculties of medicine.

Competing Interests:

Louis Valiquette reports personal fees from, and stock ownership in, Lumed Inc. He also declares personal fees from bioMérieux and grants from Roche Diagnostics outside the submitted work.

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No funding was received for this work.

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This article has been peer reviewed.