Prevalence of Antibiotic Tolerance and Risk for Reinfection Among Escherichia coli Bloodstream Isolates: A Prospective Cohort Study.

Background: Tolerance is the ability of bacteria to survive transient exposure to high concentrations of a bactericidal antibiotic without a change in the minimal inhibitory concentration, thereby limiting the efficacy of antimicrobials. The study sought to determine the prevalence of tolerance in a prospective cohort of E. coli bloodstream infection and to explore the association of tolerance with reinfection risk.

Interaction Tolerance Detection Test for Understanding the Killing Efficacy of Directional Antibiotic Combinations.

Combination treatments are commonly prescribed for enhancing drug efficacy, as well as for preventing the evolution of resistance. The interaction between drugs is typically evaluated near the MIC, using growth rate as a measure of treatment efficacy. However, for infections in which the killing activity of the treatment is important, measurements far above the MIC are needed.

Observation of universal ageing dynamics in antibiotic persistence.

Stress responses allow cells to adapt to changes in external conditions by activating specific pathways. Here we investigate the dynamics of single cells that were subjected to acute stress that is too strong for a regulated response but not lethal. We show that when the growth of bacteria is arrested by acute transient exposure to strong inhibitors, the statistics of their regrowth dynamics can be predicted by a model for the cellular network that ignores most of the details of the underlying molecular interactions.

Effect of tolerance on the evolution of antibiotic resistance under drug combinations.

Drug combinations are widely used in clinical practice to prevent the evolution of resistance. However, little is known about the effect of tolerance, a different mode of survival, on the efficacy of drug combinations for preventing the evolution of resistance. In this work, we monitored strains evolving in patients under treatment.

Tackling Antibiotic Resistance with Systems-Level Perspective.

Quantitative dissection of regulatory motifs could lead to new ways to fight antibiotic resistance.

Antibiotic tolerance facilitates the evolution of resistance.

Controlled experimental evolution during antibiotic treatment can help to explain the processes leading to antibiotic resistance in bacteria. Recently, intermittent antibiotic exposures have been shown to lead rapidly to the evolution of tolerance-that is, the ability to survive under treatment without developing resistance. However, whether tolerance delays or promotes the eventual emergence of resistance is unclear.

TDtest: easy detection of bacterial tolerance and persistence in clinical isolates by a modified disk-diffusion assay.

Antibiotic tolerance - the ability for prolonged survival under bactericidal treatments - is a potentially clinically significant phenomenon that is commonly overlooked in the clinical microbiology laboratory. Recent in vitro experiments show that high tolerance can evolve under intermittent antibiotic treatments in as little as eight exposures to high doses of antibiotics, suggesting that tolerance may evolve also in patients. However, tests for antibiotic susceptibilities, such as the disk-diffusion assay, evaluate only the concentration at which a bacterial strain stops growing, namely resistance level.

Persistence to anti-cancer treatments in the stationary to proliferating transition.

The heterogeneous responses of clonal cancer cells to treatment is understood to be caused by several factors, including stochasticity, cell-cycle dynamics, and different micro-environments. In a tumor, cancer cells may encounter fluctuating conditions and transit from a stationary culture to a proliferating state, for example this may occur following treatment. Here, we undertake a quantitative evaluation of the response of single cancerous lymphoblasts (L1210 cells) to various treatments administered during this transition.

Distinguishing between resistance, tolerance and persistence to antibiotic treatment.

Antibiotic tolerance is associated with the failure of antibiotic treatment and the relapse of many bacterial infections. However, unlike resistance, which is commonly measured using the minimum inhibitory concentration (MIC) metric, tolerance is poorly characterized, owing to the lack of a similar quantitative indicator. This may lead to the misclassification of tolerant strains as resistant, or vice versa, and result in ineffective treatments.

Direct observation of single stationary-phase bacteria reveals a surprisingly long period of constant protein production activity.

Exponentially growing bacteria are rarely found in the wild, as microorganisms tend to spend most of their lifetime at stationary phase. Despite this general prevalence of stationary-phase bacteria, they are as yet poorly characterized. Our goal was to quantitatively study this phase by direct observation of single bacteria as they enter into stationary phase and by monitoring their activity over several days during growth arrest.

Automated imaging with ScanLag reveals previously undetectable bacterial growth phenotypes.

We developed an automated system, ScanLag, that measures in parallel the delay in growth (lag time) and growth rate of thousands of cells. Using ScanLag, we detected small subpopulations of bacteria with dramatically increased lag time upon starvation. By screening a library of Escherichia coli deletion mutants, we achieved two-dimensional mapping of growth characteristics, which showed that ScanLag enables multidimensional screens for quantitative characterization and identification of rare phenotypic variants.

The importance of being persistent: heterogeneity of bacterial populations under antibiotic stress.

While the DNA sequence is largely responsible for transmitting phenotypic traits over evolutionary time, organisms are also considerably affected by phenotypic variations that persist for more than one generation, with no direct change in the organisms' DNA sequence. In contrast to genetic variation, which is passed on over many generations, the phenotypic variation generated by nongenetic mechanisms is difficult to study due to the inherently limited life time of states that are not encoded in the DNA sequence, but makes it possible for the 'memory' of past environments to influence future organisms. One striking example of phenotypic variation is the phenomenon of bacterial persistence, whereby genetically identical bacterial populations respond heterogeneously to antibiotic treatment.

The Moore's Law of microbiology - towards bacterial culture miniaturization with the micro-Petri chip.

A recent publication has reported the fabrication of a new microbial culture device containing an array of unprecedented density - a million growth chambers. This micro-Petri chip should impact on various fields, including biotechnology, ecology, food microbiology and drug development, by enabling high-throughput screens and therefore the detection of rare phenotypes within a large population of microorganisms.

Single-cell protein induction dynamics reveals a period of vulnerability to antibiotics in persister bacteria.

Phenotypic variability in populations of cells has been linked to evolutionary robustness to stressful conditions. A remarkable example of the importance of cell-to-cell variability is found in bacterial persistence, where subpopulations of dormant bacteria, termed persisters, were shown to be responsible for the persistence of the population to antibiotic treatments. Here, we use microfluidic devices to monitor the induction of fluorescent proteins under synthetic promoters and characterize the dormant state of single persister bacteria.