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Abstract Background Guidelines support the use of toxin tests after C. difficile antigen detection or nucleic acid amplification tests (e.g., PCR) to help clinicians distinguish colonization from infection and reduce overdiagnosis but the safety of toxin-based diagnostic approaches remains controversial. Methods Five California hospitals monitored hospitalized adults with C. difficile testing before and after operational changes to reduce test-related overdiagnosis (2016–2018). Four added a toxin test to an existing GDH antigen/PCR-based approach and/or changed reporting to encourage the use of toxin results for clinical decision-making (i.e.,“toxin-dominant reporting”). One used the same test (toxin only) and reporting strategy throughout. All used a standardized tool to document clinical outcomes and treatment four days after testing (i.e., Day 5). Results In total, 1,034 patients had a Day 5 assessment with PCR-dominant reporting (pre-operational changes); 2,511 patients had a Day 5 assessment with toxin-dominant reporting (post-operational changes and single facility with no test change). Fewer Toxin-negative/PCR-positive (Toxin−/PCR+) patients received treatment with toxin-dominant reporting (median change: −52.1% [interquartile range (IQR): −35.1%, −69.1%]; aggregate P < 0.001). Day 5 outcomes were similar or better with toxin-dominant reporting despite less treatment. Patient discharge rates and in hospital diarrheal recovery was greater in the subset of Toxin−/PCR+ patients during the toxin-dominant reporting period: median discharge rate change = 8.8% [IQR: 1.5%, 11.9%] (aggregate P = 0.04); median diarrheal recovery rate change = 11.8% [IQR: 8.8%, 18.2%] (aggregate P = 0.018). Conclusion In a 5-center study, toxin-dominant test result reporting decreased anti-C. difficile treatment and improved discharge rates and diarrheal recovery in Toxin−/PCR+ patients. More work is needed to determine the rate of C. difficile-related adverse events in Toxin−/PCR+ patients. Disclosures All Authors: No reported Disclosures.

BackgroundMetagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.MethodsIn a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.ResultsWe enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.ConclusionsRoutine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).