A Vicious Cycle of Antimicrobial Consumption and Resistance

Antibiotic resistance is a multifactorial problem that stems from multisectoral failures to appropriately use antimicrobials, enforce stewardship measures, and, ultimately, a lack of progress developing new drugs to treat bacterial infections. Consumption of antimicrobials is perhaps the key driver of resistance and ultimately requires changes in prescriber practices. Investigators on a new study in the journal Clinical Infectious Diseases assessed these practices when high rates of resistance were reported and found increasing resistance reciprocally affects consumption, leading to wider user of more broad-spectrum alternatives, which, in turn, limits prescribing options.

It is well known that the use of broad-spectrum drugs can lead to resistance and limit therapeutic options; however, as the relationship between drug use and resistance is likely reciprocal, it is also likely that growing resistance promotes usage of these broad-spectrum medications, while decreasing the efficacy. The research team on the CID study sought to analyze the push-pull dynamics of these practices and employed a vector autoregressive (VAR) model, which assessed the evolution of each time-series that is influenced by previous values (ie, interactions between variables are modeled at the same time and interactions between variables are assessed). The goal was to capture the cause-and-effect relationship between antimicrobial consumption and the “provoked resistance to follow up on the ongoing antibiotic resistance spiral,” the investigators wrote.

Utilizing data from a 1667-bed tertiary hospital in Hungary, the team assessed monthly consumption of all cephalosporins/third-generation cephalosporins alone, carbapenems, and colistin between October 2004 and August 2016. Antimicrobial resistance was monitored for Escherichia coli, Klebsiella spp (K pneumoniae and K oxytoca together), Pseudomonas aeruginosa, and Acinetobacter baumannii isolated from inpatients. During this time, there were no changes to infection prevention and control practices or antimicrobial stewardship activities, and if a patient had multiple isolates of the same species in the same month, it was only counted once. The research team hypothesized that consumption caused an increase in resistance against that antimicrobial, which would results in increased use of a replacement drug, which would then increase resistance to certain drugs and therefore, decrease their use.

The findings of the analysis were quite fascinating; consumption of third-generation cephalosporins was associated with increased cephalosporin resistance, which was also associated with increased carbapenem usage without a reciprocal effect in VARs (ie, cephalosporin resistance did not decrease when carbapenems were used). The carbapenem consumption then triggered resistance. “In dynamic regression but not in VARs, consumption of cephalosporins 3 months earlier (coefficient 0.07) and fluoroquinolones 4 months earlier (coefficient 0.02) also contributed to increases in carbapenem resistance, while aminoglycosides used in the same month and 3 months earlier were protective (cumulated coefficients -0.19, data not shown),” the investigators found.

The results revealed the antibiotic resistance spiral that the investigators hypothesized—increasing resistance to cephalosporin triggered an increase in carbapenem consumption. This increased consumption of carbapenems also resulted in increasing antimicrobial resistance to the drug. In response to growing carbapenem resistance, colistin consumption increased. Use of colistin led to a decrease in carbapenem consumption and carbapenem resistance of P aeruginosa (but not A baumannii).

This study gives support to a practice so many of us have witnessed—a vicious cycle of resistance and resulting antimicrobial consumption that does little to slow the problem. The investigators noted the importance of modifying prescribing habits to better understand this cyclical relationship. Prescribing behavior without close pharmacy discussion and antimicrobial stewardship consideration can result in improper use of antimicrobials that fuel resistance. Understanding the dynamics of prescribing practices, and how avoidance of resistance may provoke further resistance, is critical to reducing the burden of antimicrobial resistance overall.