bIn this study, we introduce a new approach for determination of epidemiologic cutoffs (ECOFFs) and resistant-population cutoffs (RCOFFs) based on receiver operating characteristic (ROC) curves. As an example, the method was applied for determination of ECOFFs for seven different beta-lactam antibiotics and wild-type populations of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. In addition, RCOFFs were determined for bacterial populations with defined resistance mechanisms ("resistotypes"), i.e., extended-spectrum beta-lactamase (ESBL)-positive E. coli, ESBL-positive K. pneumoniae, and ESBL-positive E. cloacae; AmpC cephalosporinase-positive E. coli and AmpC-positive K. pneumoniae; and broad-spectrum beta-lactamase (BSBL)-positive E. coli. RCOFFs and ECOFFs are instrumental for a systematic characterization of associations between resistotypes and wild-type populations.
In antimicrobial susceptibility testing (AST), clinical isolates are classified as resistant or susceptible on the basis of clinical breakpoints (CBPs), i.e., a threshold inhibition zone diameter size to which the treatment outcome is correlated. Organizations such as the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI) recommend CBPs for a wide range of antibiotic-pathogen combinations (1, 2). CBPs are derived from a combination of pharmacokinetic and pharmacodynamic (PK/PD) data, clinical outcome data, and in vitro MIC data (3, 4). EUCAST has revived the concept of the microbiological breakpoint proposed by Williams (5) and introduced the epidemiological cutoff (ECOFF), which is used as microbiological evidence in the process of CBP setting. EUCAST defined the ECOFF as "the upper MIC value of the wild-type distribution" and as the cutoff which "separates microorganisms without (wild-type) and with acquired resistance mechanisms (non-wild-type) to the agent in question" (1, 3). In an accompanying paper, Valsesia et al. (6) argue that in order to improve the description of antimicrobial susceptibility patterns in bacterial populations, the relationship between wild-type and non-wild-type populations should be considered. A complementary cutoff term is proposed for this purpose: the resistantpopulation cutoff (RCOFF). The RCOFF is defined as the largest inhibition zone diameter (or the lowest MIC) that delineates a non-wild-type population and complements the ECOFF for improved discrimination of populations carrying a resistance mechanism (the "resistotypes") from wild-type bacterial populations.To date, several methods have been proposed to determine inhibition zone diameter cutoffs, such as the error rate-bounded method (7), a modified error rate-bounded method (8), the normalized resistance interpretation method (9, 10), and few statistical inference approaches (11,12). However, visual inspection of distributions (eyeball method) has usually been applied to determine cutoffs (12)(13)(14)(15)(16). While this method can be applied for cutoff estimat...