Utilization of Vector Autoregressive and Linear Transfer Models to Follow Up the Antibiotic Resistance Spiral in Gram-negative Bacteria From Cephalosporin Consumption to Colistin Resistance

BACKGROUND: Increasing antibiotic resistance may reciprocally affect consumption and lead to use of broader-spectrum alternatives; a vicious cycle that may gradually limit therapeutic options. Our aim in this study was to demonstrate this vicious cycle in gram-negative bacteria and show the utility of vector autoregressive (VAR) models for time-series analysis in explanatory and dependent roles simultaneously. METHODS: Monthly drug consumption data in defined daily doses per 100 bed-days and incidence densities of gram-negative bacteria (Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter baumannii) resistant to cephalosporins or to carbapenems were analyzed using VAR models. These were compared to linear transfer models used earlier. RESULTS: In case of all gram-negative bacteria, cephalosporin consumption led to increasing cephalosporin resistance, which provoked carbapenem use and consequent carbapenem resistance and finally increased colistin consumption, exemplifying the vicious cycle. Different species were involved in different ways. For example, cephalosporin-resistant Klebsiella spp. provoked carbapenem use less than E. coli, and the association between carbapenem resistance of P. aeruginosa and colistin use was weaker than that of A. baumannii. Colistin use led to decreased carbapenem use and decreased carbapenem resistance of P. aeruginosa but not of A. baumannii. CONCLUSIONS: VAR models allow analysis of consumption and resistance series in a bidirectional manner. The reconstructed resistance spiral involved cephalosporin use augmenting cephalosporin resistance primarily in E. coli. This led to increased carbapenem use, provoking spread of carbapenem-resistant A. baumannii and consequent colistin use. Emergence of panresistance is fueled by such antibiotic-resistance spirals.