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The U.S. Food & Drug Administration (FDA) regulates the marketing of manufacturers’ in vitro diagnostic tests (IVDs), including assays for the detection of SARS-CoV-2. The U.S. government’s Clinical Laboratory Improvement Amendments (CLIA) of 1988 regulates the studies that a clinical diagnostic laboratory needs to perform for an IVD before placing it into use. Until recently, the FDA has authorized the marketing of SARS-CoV-2 IVDs exclusively through the Emergency Use Authorization (EUA) pathway. The regulatory landscape continues to evolve, and IVDs will eventually be required to pass through conventional non-EUA FDA review pathways once the emergency declaration is terminated, in order to continue to be marketed as an IVD in the United States. When FDA regulatory status of an IVD changes or is anticipated to change, the laboratory should review manufacturer information and previously performed internal verification studies to determine what, if any, additional studies are needed before implementing the non-EUA version of the IVD in accordance with CLIA regulations. Herein, the College of American Pathologists’ Microbiology Committee provides guidance for how to approach regulatory considerations when an IVD is converted from EUA to non-EUA status.

On behalf of the Microbiology Committee of the College of American Pathologists (CAP), we respond to the recent commentary by Kirby and colleagues on the topic of bringing in new antimicrobial susceptibility testing ([1][1]). The authors state that “there is a lack of clarity regarding

Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) are commonly ordered in clinical practice to evaluate for inflammation. CRP is a more sensitive and specific test for detecting acute phase inflammation, and the American Society for Clinical Pathology recommends ordering CRP rather than ESR to detect acute phase inflammation in patients with undiagnosed conditions. We sought to understand CRP and ESR ordering practices and reduce unnecessary use of ESR testing at our academic medical centre. We surveyed physician leaders in clinical areas with high utilisation of ESR testing to understand the drivers of potential overutilisation of these tests. Based on survey responses, we designed an intervention focused on education, clinical decision support within the electronic medical record and quarterly audit and feedback. We evaluated appropriateness of ESR ordering before and after the intervention via structured chart audit. Comparison of monthly rates of ESR tests during the preintervention and postintervention periods was conducted using interrupted time series analysis. Clinical habit and ease of test ordering were identified as key drivers of ESR overuse. Compared with the preintervention period, we observed a 33% reduction in the number of ESR tests per month and a 25% reduction in combined CRP and ESR tests per month during the postintervention period. This reduction corresponded to an annual avoidance of 2633 ESR tests with a corresponding estimated direct cost avoidance of $23 701 annually. Although the rate of ESR testing decreased, there was no significant improvement in the clinical appropriateness of residual ESR test ordering following the intervention. A multifaceted intervention was associated with significant decreases in unnecessary ESR tests and concurrent ESR and CRP tests at our academic medical centre. Despite these reductions, there are continued opportunities to reduce inappropriate ESR testing.

Clostridium difficile is a major contributor to morbidity and mortality in the United States. Methods for identifying the organism in stool include molecular platforms, enzyme immunoassays (EIAs) for toxin, and culture. Controversy persists over whether molecular tests are too sensitive at identifying C. difficile , and there are questions about how additional laboratory information could inform clinical management and reduce over treatment. The aim of this study was to assess whether clinical factors are related to the toxin status of patients and whether information about toxin status could potentially inform clinical management of patients. A total of 201 PCR-positive C. difficile stool samples from adult patients at our institution underwent EIA toxin testing. Clinical and laboratory data were collected, and the percentage of PCR-positive/EIA-positive (PCR + /EIA + ) patients and PCR + and EIA-negative (PCR + /EIA − ) patients was calculated. Of the 201 samples, 47% were EIA positive and 53% were EIA negative. Although PCR + /EIA + patients were more likely to have had a prior C. difficile infection ( P = 0.015), there was no statistical difference between the additional data collected that correlated with a positive EIA result. We were unable to show that patients with an EIA + result had worse clinical parameters than those with EIA − results and concluded that establishing a testing algorithm that included both PCR and EIA testing would not change the clinical management of patients at our hospital.

Objectives: Traditional microbial identification methods are based on morphology (both micro- and macroscopic) and biochemical tests that require long incubation periods and a good deal of technologist hands-on time. In addition, many of these methods have some degree of subjectivity. In comparison, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) identifies microorganisms from colonies grown on solid media within minutes using very few reagents. Methods: A case-based approach was used to review the strengths and weaknesses of MALDI-TOF MS in clinical microbiology laboratories. Results: MALDI-TOF MS has been proven to be an accurate and reliable method for organism identification including bacteria, yeast, molds, and mycobacteria. It is rapid, with results often 24 hours earlier than traditional methods, and inexpensive. There are no FDA-approved systems available currently. Susceptibility data are still reliant on conventional methods. There are genetically similar organisms that cannot be discriminated reliably with this method. Conclusions: MALDI-TOF MS is an exciting, innovative method for organism identification in the clinical microbiology laboratory.

An increasing spectrum and number of opportunistic fungal pathogens have been reported to cause disease in humans over the past decade. Disseminated phaeohyphomycoses caused by rare dematiaceous molds in immunocompromised patients have a high mortality rate and are increasingly reported in the literature. Early diagnosis of disseminated phaehyphomycosis is critical especially in neutropenic patients but can be hindered by the low sensitivity of fungal blood cultures and low clinical suspicion. Cutaneous manifestations are often the earliest sign of disease and conducting a thorough skin exam in febrile neutropenic patients can lead to more rapid diagnosis and initiation of treatment. PCR amplification and sequencing of mold RNA extracted from paraffin-embedded tissue can be useful for diagnosing rare fungal infections when negative fungal cultures preclude morphologic diagnosis. Effective treatment for disseminated phaehyphomycosis is lacking and there is a need to report experiences with the use of newer antifungals.

Rapid identification of pathogens from blood cultures can decrease lengths of stay and improve patient outcomes. We evaluated the accuracy of the Verigene Gram-positive blood culture (BC-GP) nucleic acid test for investigational use only (Nanosphere, Inc., Northbrook, IL) for the identification of Gram-positive bacteria from blood cultures. The detection of resistance genes ( mecA in Staphylococcus aureus and Staphylococcus epidermidis and vanA or vanB in Enterococcus faecium and Enterococcus faecalis ) by the BC-GP assay also was assessed. A total of 186 positive blood cultures (in BacT/Alert FA bottles) with Gram-positive cocci observed with Gram staining were analyzed using the BC-GP assay. The BC-GP results were compared with the identification and susceptibility profiles obtained with routine methods in the clinical laboratory. Discordant results were arbitrated with additional biochemical, cefoxitin disk, and repeat BC-GP testing. The initial BC-GP organism identification was concordant with routine method results for 94.6% of the blood cultures. Only 40% of the Streptococcus pneumoniae identifications were correct. The detection of the mecA gene for 69 blood cultures with only S. aureus or S. epidermidis was concordant with susceptibility testing results. For 3 of 6 cultures with multiple Staphylococcus spp., mecA detection was reported but was correlated with oxacillin resistance in a species other than S. aureus or S. epidermidis . The detection of vanA agreed with susceptibility testing results for 45 of 46 cultures with E. faecalis or E. faecium . Comparison of the mean times to results for each organism group showed that BC-GP results were available 31 to 42 h earlier than phenotypic identifications and 41 to 50 h earlier than susceptibility results.