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The purpose of this study was to assess the clinical impact of the BioFire FilmArray Meningitis/Encephalitis (ME) panel on antimicrobial use and clinical outcomes. This retrospective, quasi-experiment evaluated adult and pediatric patients with suspected ME, evidenced by cerebrospinal fluid (CSF) culture. Hospital-acquired meningitis patients and patients who received antimicrobials >48 h prior to lumbar puncture were excluded. The primary endpoint was days of antimicrobial therapy pre- and post-implementation of the ME panel. Secondary endpoints included total length of stay, 30-day readmission, and individual days of antimicrobial therapy. Two hundred and sixty-four total adult and pediatric patients were included. Antimicrobial days of therapy had a median of 3 days (IQR 0−5) in the pre vs. post group with a median of 2 days (2−5) (p = 0.099). Days of therapy for acyclovir were significantly decreased in the post group (median 2 days [IQR 1−3] vs. 3 days [IQR 2.5−4.5], p = 0.0002). There were no significant differences in the secondary endpoints. Overall, implementation of the ME panel impacted the duration of antimicrobials, particularly acyclovir; however, opportunities for further education regarding antimicrobial de-escalation and utilization of the panel were identified. Antimicrobial stewardship program intervention is critical to maximize benefit of this rapid diagnostic test.

In a continuation of studies directed at characterizing the conformational basis of binding beta-phenylethylamines at the active site of phenylethanolamine N-methyltransferase (PNMT), anti-10-amino- (12) and syn-10-amino-5,6,7,8-tetrahydro-5,8-methano-9H-benzocycloheptene (13) were prepared and evaluated as substrates and inhibitors for PNMT. These conformationally defined amphetamine analogues mimic a low energy half-chair form of 2-aminotetralin (2AT). Further, in order to determine the active site binding orientation of beta-phenylethylamines bearing aryl lipophilic substituents, the aryl trifluoromethyl-substituted derivatives of 12 and 13 (20-27), as well as anti-9-amino-5-(trifluoromethyl)-(18) and anti-9-amino-6-(trifluoromethyl) benzonorbornene (19), were prepared and evaluated. The competitive inhibition displayed by the fully extended analogue 12 coupled with the uncompetitive kinetics exhibited by the folded isomer 13 supports previous findings that a fully extended side chain conformation is optimal for binding to the active site of PNMT. In addition, the fact that 12 displayed enhanced affinity as an inhibitor over its beta-phenylethylamine counterparts in the benzonorbornene and 1,4-ethanonaphthalene ring systems suggests that a half-chair conformation is preferred when 2AT analogues interact at the active site of the enzyme. This would be consistent with previous results that PNMT preferentially binds molecules with a more coplanar relationship between the aromatic ring and the amino nitrogen. The lack of activity as a substrate in 12 indicates that the negative steric interactions of the ethano bridging unit prohibits it from binding in a manner consistent with the known PNMT substrates exo-2-amino- (6) and anti-9-aminobenzonorbornene (8). Given the emergence of activity as a substrate in 20 and 21 (the 1-trifluoromethyl- and the 2-trifluoromethyl-substituted derivatives of 12), it appears that the positive interaction of the trifluoromethyl group orients these analogues in a manner in which the ethano bridge lies in regions of steric bulk tolerance. This would suggest that the region of steric intolerance has a degree of directionality. Finally, although the aromatic ring binding region of the active site of PNMT contains a large degree of lipophilic character, only specific spatial orientations between the trifluoromethyl group and the amino nitrogen of aryl trifluoromethyl-substituted beta-phenylethylamines allow both to interact simultaneously in a manner that allows the amine to bind in a region of the active site in which methylation can occur.