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Antimicrobial stewardship practices are critical in preventing the further erosion of treatment options for bacterial infections. Yet, at the same time, determination of an infection's antimicrobial susceptibility requires multiple rounds of culture and expensive lab automation systems. In this work, we report the use of paper-based surface enhanced Raman spectroscopy (SERS) sensors and portable instrumentation to phenotypically discriminate multi-drug resistance with fewer culture steps than conventional clinical microbiology. Specifically, we demonstrate the identification of resistance to varying generations of β -lactam antibiotics by detecting the activity of particular β -lactamase enzymes in a multiplexed assay. The method utilizes molecular reporters that consist of β -lactams with SERS barcodes. Hydrolysis of the β -lactam by β -lactamase enzymes in the sample expels the barcode; the released sulfur-containing barcode is then detected via SERS. Using this approach, we demonstrate the differentiation of E. coli strains with (1) extended spectrum β -lactamase (ESBL), (2) narrow-spectrum β -lactamase, and (3) no resistance, using only a single measurement on a single sample. In addition, we experimentally validate an approach to expand the library of reporters through the simple chemical synthesis of new barcoded β -lactams. Importantly, the reported method determines the susceptibility based on phenotypic β -lactamase activity, which is aligned with current microbiology lab standards. This new method will enable the precise selection of effective β -lactam antibiotics (as opposed to defaulting to drugs of last resort) faster than current methods while using simple steps and low-cost portable instrumentation. Image 1 • We demonstrate phenotypic detection of β-lactamase activity using paper SERS sensors and portable instrumentation. • We show discrimination of β -lactamases with different degrees of resistance in a single sample on a single sensor. • We demonstrate a simple synthesis method to expand the library of SERS-based β -lactamase reporters. • We accomplish β-lactamase discrimination in significantly less time than conventional microbiology. [ABSTRACT FROM AUTHOR]