Do Antidepressants Facilitate Antimicrobial Resistance?

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Article
Infection Control TodayInfection Control Today, April 2023, (Vol. 27, No. 3)
Volume 27
Issue 3

A new study shows antibiotics are not the only widely used pharmaceuticals that can induce the emergence of treatment-resistant bacteria.

Antimicrobial resistance

Antimicrobial resistance

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This article first appeared in Contagion.Live.

Antidepressants appeared to induce antimicrobial resistance (AMR) and “persistence” in ostensibly susceptible bacteria in a multifaceted assessment of bacterial cultures challenged by antibiotics after exposure to clinically relevant concentrations of antidepressants.

“Although antibiotic resistance has become a major threat to human health worldwide, the phenomenon caused by antidepressants has been largely overlooked,” observed Jianhua Guo, DEng, Australian Centre for Water and Environmental Biotechnology, The University of Queensland, Brisbane, QLD, Australia, and colleagues.

“Our findings illustrate how antidepressants induce bacterial resistance and persistence to a range of antibiotics,” they indicate. "The antibiotic persistence (higher tolerance) helps to maintain bacterial resistance, and the persisters could evolve to resistant bacteria during the long-term evolutionary process,” Guo and colleagues explain.

In his profile at the University of Queensland, Guo and his team are credited for the “ground-breaking findings” that non-antibiotic pharmaceuticals/chemicals contribute to the spread of antimicrobial resistance, “which has substantially augmented our understanding of the causes of AMR.”

The investigators’ interest in the possibility arose from the evidence that antidepressants modify the gut microbiota; their current investigation follows from having found AMR after exposing bacteria to the antidepressant fluoxetine. They conducted the current research to ascertain whether that finding reflects a drug-specific action or is common to other antidepressants and to identify possible mechanisms.

Guo and colleagues utilized E coli plate culturing under both aerobic and anaerobic conditions, fluorescence-based flow cytometry detection, and genome-wide analyses to discern changes in antibiotic susceptibility after antidepressant exposure. They tested the commonly prescribed antidepressants representing different classes, sertraline, escitalopram, bupropion, and duloxetine, as well as agomelatine, from an additional class of antidepressant not approved in the US.

Exposure to the antidepressants was found to increase the production of intracellular reactive oxygen species (ROS) and induce efflux pump expression; both of which the investigators correlate to the emergence of antibiotic-resistant and persistent phenotypes. In addition, they determined that conjugative gene transfer was promoted.

“Together, our findings describe a mechanism by which exposure to antidepressants can lead to enhanced resistance to antibiotics,” the investigators indicated.

After only 1 day of exposure to sertraline and duloxetine at a concentration typical in the colon, the ratio of resistant cells to total cell number was more than 10,000-fold compared to the non-antidepressant control. Guo and colleagues point out that this was a greater magnitude of emergence than others have found with several sub-inhibitory antibiotics, including nalidixic acid, ampicillin, rifampicin, and carbenicillin.

The resistant traits were determined to be heritable, but the rate and magnitude of effect were not constant across all antidepressants. In contrast to sertraline and duloxetine, bupropion, escitalopram, and agomelatine were found to exert “limited” effects on resistance. These were associated with up to eightfold growth of resistant cells relative to the non-antidepressant control, which was at higher concentrations of the antidepressants (100 mg/L).

In phenotypic and genotypic analyses, the investigators determined that induced resistance with sertraline and duloxetine was associated with enhanced ROS generation and that this did not occur in anaerobic conditions. Sertraline and duloxetine were also found to enhance efflux pump expression, which, the investigators point out, is one of the principal mechanisms of the cell expelling antibiotics and reducing susceptibility.

The investigators indicate that their findings implicate antidepressants as a contributing driver of the increasing AMR. They suggest that additional studies should be conducted to validate the effects, employing more bacterial strains and possibly conducted in-vivo in the gut microbiota.

“The findings might be also useful for pharmaceutical factories and public health organizations to comprehensively evaluate antimicrobial sides of antidepressants,” Guo and colleagues indicate.

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