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

Abstract

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.

The Role of Uniform Meropenem Usage in Acinetobacter baumannii Clone Replacement

“…This evolution towards more efficient hydrolysis of carbapenems is linked to increasing use of carbapenems in many countries, as documented earlier in this setting [17] and elsewhere [28][29][30][31]. This relationship is the inherent part of the Gram-negative resistance spiral, as carbapenem usage increases in response to the spread of extended spectrum β-lactamase (ESBL) producing Enterobacterales in our setting [32]. The link between the strain switch and carbapenem use is further supported by the coincident changepoints.…”

Evolution of the Gram-Negative Antibiotic Resistance Spiral over Time: A Time-Series Analysis

“…Thus, the present study represents an attempt to track the changes in the resistance spiral over time. The temporally stable dynamics of the Gram-negative resistance spiral supports that antibiotic resistance is shifting towards increasing resistance in Gram-negative bacteria continuously, as extensively documented both at local [ 8 , 34 , 35 ] and global [ 36 , 37 , 38 ] scales. This spread of resistance is driven, at least partly, by the turning of the prescribers’ preference towards broader and broader spectrum antibiotics, as concluded earlier [ 4 , 8 , 32 ].…”

“…This resistance spiral was shown to involve multiple species; emerging cephalosporin resistance in Escherichia coli induced increasing preference for carbapenem prescribing, which led to increased carbapenem resistance in Pseudomonas aeruginosa and in Acinetobacter baumannii . Concern about carbapenem resistance provoked an increased prescribing of colistin as the last-resort drug [ 8 ].…”

“…This work, as an extension of our abovementioned earlier study reporting a snapshot of the resistance spiral [ 8 ], attempts to capture the evolution of the resistance spiral over time by examining relationships among drug consumption and resistance and by comparing the interactions between drugs and drug-resistant bacteria at four additional time points.…”

Challenges and opportunities for antimicrobial stewardship in resource-rich and resource-limited countries

“…This is likely a result of the rising rates of AMR itself (Center for Disease Dynamics, Economics & Policy, 2015). This AMR spiral has been evidenced in vector-autoregression based time-series models(Toth et al, 2018). However, the escalating use of broad-spectrum antibiotics is not always justified and partly reflects failures instewardship.…”