How non-adherence encourages antibiotic tolerance

New research on antibiotic-tolerant bacteria has underlined the importance of medicines compliance

Researchers have developed a simple new method for measuring the time it takes to kill bacteria that have become tolerant to antibiotic drugs.

Tolerance is the first step towards diseases developing full resistance to antibiotics.

The new findings should allow doctors to ensure they are prescribing antibiotics for the correct length of time to prevent antibiotic resistance developing, say the Israeli and American researchers.

“These findings allow measurement of tolerance, which has previously been largely overlooked in the clinical setting,” says senior study author Nathalie Balaban of The Hebrew University of Jerusalem.

“Routinely measuring tolerance could supply valuable information about the duration of antibiotic treatments, reducing the chance of both under- and over-treatment.

“Furthermore, data compiled from such measurements could give an estimate of how widespread the phenomenon of tolerance really is, which is currently a complete unknown.”

Due to selective pressure, pathogens acquire resistance through mutations that make the antibiotic less effective, for example, by interfering with the ability of a drug to bind to its target. Currently, clinicians determine which antibiotic and dose to prescribe by assessing resistance levels using the routine metric minimum inhibitory concentration (MIC)—the minimal drug concentration required to prevent bacterial growth.

Although resistant strains continue to grow despite exposure to high drug concentrations, tolerant strains can survive lethal concentrations of an antibiotic for a long period of time before succumbing to its effects. Tolerance is often associated with treatment failure and relapse, and it is considered a stepping stone toward the evolution of antibiotic resistance.

But unlike resistance, tolerance is poorly understood and is currently not evaluated in healthcare settings.

“The lack of a quantitative measure means that this aspect of the treatment relies largely on the experience of the individual physician or the community,” says first author Asher Brauner, a PhD student in Prof Balaban’s laboratory.

“This can lead to treatment being either too short, increasing the risk of relapse and evolution of resistance, or much too long, unnecessarily causing side effects, release of antibiotic waste into the environment, and additional costs.”

The team developed a tolerance metric called the minimum duration for killing 99% of the population (MDK99).

The  protocol, which can be performed manually or using an automated robotic system, involves exposing populations of approximately 100 bacteria in separate microwell plates to different concentrations of antibiotics for varied time periods, while determining the presence or lack of survivors.

The researchers applied MDK99 to six Escherichia coli strains, which showed tolerance levels ranging from two to 23 hours under ampicillin treatment.

MDK99 also facilitates measurements of a special case of tolerance known as time-dependent persistence—the presence of transiently dormant subpopulations of bacteria that are killed more slowly than the majority of the fast-growing population. Like other forms of tolerance, time-dependent persistence can lead to recurrent infections because the few surviving bacteria can quickly grow to replenish the entire population once antibiotic treatment stops.

“A take-home message from this is that it is important to complete a course of antibiotic treatment as prescribed, even after the disappearance of the symptoms,” Prof Balaban says.

“Partial treatment gives tolerance and persistence mutations a selective advantage, and these, in turn, hasten the development of resistance.”

In future studies, Prof Balaban and her team plan to use MDK99 to study the evolution of tolerance in patients. Moreover, the ability to systematically determine the tolerance level of strains in the lab could facilitate research in the field, they say.

“If implemented in hospital clinical microbiology labs, MDK99 could enable the efficient classification of bacterial strains as tolerant, resistant, or persistent, helping to guide treatment decisions,” Prof Balaban says.

“In the end, understanding tolerance and finding a way to combat it could significantly reduce the ever-growing risk of resistance.”

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