A simple new method has been developed
for measuring the time it takes to kill a bacterial population could improve
the ability of clinicians to effectively treat antimicrobial-tolerant strains
that are on the path to becoming resistant.
According to the World Health
Organization, antibiotic resistance is one of the biggest threats to global
health and is putting the achievements of modern medicine at risk. 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 a routine metric
called 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.
To address this problem, researchers
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 2 to 23 hr
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.
In future studies, the researchers
will 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.
See:
Posted by Dr. Tim Sandle
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Pharmaceutical Microbiology