Editors' ChoicePOSTANTIBIOTIC EFFECT

To grow or not to grow: Postantibiotic effect is the question

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Science Translational Medicine  29 Nov 2017:
Vol. 9, Issue 418, eaar2442
DOI: 10.1126/scitranslmed.aar2442

Abstract

Temporary inhibition of Escherichia coli growth in vitro after antibiotic administration is proportional to total antibiotic quantity.

One challenge of bacterial microbiologic diagnosis is when bacteria are present but don’t grow on appropriate growth media. A possible reason for this impaired growth is receipt of antibiotic prior to specimen collection for culture. In a recent article, Srimani et al. explored this postantibiotic effect, defined as temporary growth inhibition of bacteria after transient antibiotic exposure. In vivo, such inhibition can provide opportunities for a person’s immune system to work against the bacteria, which is particularly important with the emergence and spread of multidrug-resistant bacteria.

The authors used a microfluidics platform to generate monolayers of Escherichia coli expressing green fluorescent protein so that growth could be monitored by fluorescence. E. coli monolayers were treated with antibiotics at different concentrations and with different dosing intervals. Recovery time, defined as the time from end of antibiotic dosing to population doubling, increased with increasing antibiotic exposure regardless of how the antibiotic was dosed. To study the dynamics of postantibiotic effect, the authors used mathematical models to consider factors impacting bacterial recovery, including efflux of antibiotics and post-exposure ribosomal recovery. Another series of microfluidic experiments confirmed the association of these factors with increased time to recovery. Efflux pump inhibition with a phosphorylation inhibitor increased recovery times when co-administered with chloramphenicol. Correspondingly, an antibiotic that causes ribosome degradation extended recovery time compared to one that does not.

The authors hypothesized that their postantibiotic effect model is applicable to any antibiotic with an intracellular target. They then modeled and measured recovery times at increasing concentrations of antibiotics acting in 3 pathway types: target degradation with antibiotic (aminoglycosides), target binding without degradation (fluoroquinolones), and unmodified target synthesis (beta-lactams). For all antibiotics, E. coli recovery time was proportional to the quantity of antibiotic exposure. Concomitant efflux inhibitor increased the recovery time most for those antibiotics that degrade an intracellular target with a positive feedback loop. These findings have important implications for determining ideal antibiotic regimens, particularly for intermittent dosing intervals. Additionally, this paper’s methodology could be used to screen for pharmacologic adjuvants to prolong the postantibiotic effect.

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