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Journal ArticleDOI

Selection of resistant bacteria at very low antibiotic concentrations.

21 Jul 2011-PLOS Pathogens (Public Library of Science)-Vol. 7, Iss: 7
TL;DR: It is suggested that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.
Abstract: The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.

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Citations
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Journal ArticleDOI
TL;DR: The aim of the present paper is to critically review the fate and removal of various antibiotics in wastewater treatment, focusing on different processes (i.e. biological processes, advanced treatment technologies and disinfection) in view of the current concerns related to the induction of toxic effects in aquatic and terrestrial organisms.

1,516 citations


Cites background from "Selection of resistant bacteria at ..."

  • ...However, it remains unclear where most of the resistant bacteria have been selected, and in particular if the low antibiotic concentrations that are present in natural environments or in human/animal body compartments during therapeutic use, are important for the selection and enrichment of resistant mutants (Gullberg et al., 2012)....

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  • ...…of the resistant bacteria have been selected, and in particular if the low antibiotic concen- trations that are present in natural environments or in human/animal body compartments during therapeutic use, are important for the selection and enrichment of resistant mutants (Gullberg et al., 2012)....

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Journal ArticleDOI
TL;DR: The main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment are discussed.
Abstract: Antibiotic resistance is a threat to human and animal health worldwide, and key measures are required to reduce the risks posed by antibiotic resistance genes that occur in the environment. These measures include the identification of critical points of control, the development of reliable surveillance and risk assessment procedures, and the implementation of technological solutions that can prevent environmental contamination with antibiotic resistant bacteria and genes. In this Opinion article, we discuss the main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment.

1,495 citations

Journal ArticleDOI
TL;DR: The ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance are discussed and the effects of low-level drug exposure on bacterial physiology are considered, including the generation of genetic and phenotypic variability, as well as the able of antibiotics to function as signalling molecules.
Abstract: The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

1,226 citations

Journal ArticleDOI
TL;DR: Although the economics of the pharmaceutical industry continue to restrict investment in novel biomedical responses, action must be taken to avoid the conjunction of factors that promote evolution and spread of antibiotic resistance.
Abstract: During the past 10 years, multidrug-resistant Gram-negative Enterobacteriaceae have become a substantial challenge to infection control. It has been suggested by clinicians that the effectiveness of antibiotics is in such rapid decline that, depending on the pathogen concerned, their future utility can be measured in decades or even years. Unless the rise in antibiotic resistance can be reversed, we can expect to see a substantial rise in incurable infection and fatality in both developed and developing regions. Antibiotic resistance develops through complex interactions, with resistance arising by de-novo mutation under clinical antibiotic selection or frequently by acquisition of mobile genes that have evolved over time in bacteria in the environment. The reservoir of resistance genes in the environment is due to a mix of naturally occurring resistance and those present in animal and human waste and the selective effects of pollutants, which can co-select for mobile genetic elements carrying multiple resistant genes. Less attention has been given to how anthropogenic activity might be causing evolution of antibiotic resistance in the environment. Although the economics of the pharmaceutical industry continue to restrict investment in novel biomedical responses, action must be taken to avoid the conjunction of factors that promote evolution and spread of antibiotic resistance.

893 citations

Journal ArticleDOI
TL;DR: This review presents the current understanding of the molecular mechanisms of biofilm recalcitrance toward antibiotics and describes how recent progress has improved the capacity to design original and efficient strategies to prevent or eradicate biofilm-related infections.
Abstract: Surface-associated microbial communities, called biofilms, are present in all environments. Although biofilms play an important positive role in a variety of ecosystems, they also have many negative effects, including biofilm-related infections in medical settings. The ability of pathogenic biofilms to survive in the presence of high concentrations of antibiotics is called "recalcitrance" and is a characteristic property of the biofilm lifestyle, leading to treatment failure and infection recurrence. This review presents our current understanding of the molecular mechanisms of biofilm recalcitrance toward antibiotics and describes how recent progress has improved our capacity to design original and efficient strategies to prevent or eradicate biofilm-related infections.

862 citations


Cites background from "Selection of resistant bacteria at ..."

  • ...Although it is generally assumed that selection of resistant bacteria occurs at antibiotic concentrations between the MIC of the susceptible wild-type population and that of the resistant bacteria, recent studies suggested that such selection could also occur at lower antibiotic concentrations (168)....

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References
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Journal ArticleDOI
16 Aug 2002-Science
TL;DR: This work constructed strains of Escherichia coli that enable detection of noise and discrimination between the two mechanisms by which it is generated and reveals how low intracellular copy numbers of molecules can fundamentally limit the precision of gene regulation.
Abstract: Clonal populations of cells exhibit substantial phenotypic variation. Such heterogeneity can be essential for many biological processes and is conjectured to arise from stochasticity, or noise, in gene expression. We constructed strains of Escherichia coli that enable detection of noise and discrimination between the two mechanisms by which it is generated. Both stochasticity inherent in the biochemical process of gene expression (intrinsic noise) and fluctuations in other cellular components (extrinsic noise) contribute substantially to overall variation. Transcription rate, regulatory dynamics, and genetic factors control the amplitude of noise. These results establish a quantitative foundation for modeling noise in genetic networks and reveal how low intracellular copy numbers of molecules can fundamentally limit the precision of gene regulation.

5,209 citations

Journal ArticleDOI
TL;DR: This review brings up important questions that are still open, and addresses some significant issues which must be tackled in the future for a better understanding of the behavior of antibiotics in the environment, as well as the risks associated with their occurrence.

3,620 citations


"Selection of resistant bacteria at ..." refers background in this paper

  • ...aquatic or soil) environments [8,9,10], that are produced naturally by antibiotic-producing micro-organisms or that are present in certain human/animal body compartments during therapeutic or growth promotion use, are for the selection and enrichment of resistant mutants....

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  • ...environments or in soil levels are typically much lower [8]....

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Journal ArticleDOI
TL;DR: Global efforts are needed to promote more judicious use of prophylactic antibiotics in aquaculture as accumulating evidence indicates that unrestricted use is detrimental to fish, terrestrial animals, and human health and the environment.
Abstract: Summary The accelerated growth of finfish aquaculture has resulted in a series of developments detrimental to the environment and human health. The latter is illustrated by the widespread and unrestricted use of prophylactic antibiotics in this industry, especially in developing countries, to forestall bacterial infections resulting from sanitary shortcomings in fish rearing. The use of a wide variety of antibiotics in large amounts, including non-biodegradable antibiotics useful in human medicine, ensures that they remain in the aquatic environment, exerting their selective pressure for long periods of time. This process has resulted in the emergence of antibiotic-resistant bacteria in aquaculture environments, in the increase of antibiotic resistance in fish pathogens, in the transfer of these resistance determinants to bacteria of land animals and to human pathogens, and in alterations of the bacterial flora both in sediments and in the water column. The use of large amounts of antibiotics that have to be mixed with fish food also creates problems for industrial health and increases the opportunities for the presence of residual antibiotics in fish meat and fish products. Thus, it appears that global efforts are needed to promote more judicious use of prophylactic antibiotics in aquaculture as accumulating evidence indicates that unrestricted use is detrimental to fish, terrestrial animals, and human health and the environment.

1,947 citations


"Selection of resistant bacteria at ..." refers background in this paper

  • ...Whereas some resistance-conferring genes were most likely originally selected to serve metabolic functions and/or for signal trafficking or protection against competing antibiotic-producing bacteria [4], the recent worldwide enrichment and spread of highly resistant pathogenic bacteria in the micro-biosphere has largely been driven by human activities, including the extensive use and misuse of antibiotics in human and veterinary medicine and in agriculture [2,3,5,6,7]....

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Journal ArticleDOI
TL;DR: The findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced, and that the rate of reversibility will be slow at the community level.
Abstract: Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.

1,929 citations


"Selection of resistant bacteria at ..." refers background in this paper

  • ...However, in most resistant strains found clinically the fitness cost of resistance is frequently compensated for by secondary mutations without a loss of resistance [25]....

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Journal ArticleDOI
18 Jul 2008-Science
TL;DR: The large majority of antibiotics currently used for treating infections and the antibiotic resistance genes acquired by human pathogens each have an environmental origin and the function of these elements in their environmental reservoirs may be very distinct from the “weapon-shield” role they play in clinical settings.
Abstract: The large majority of antibiotics currently used for treating infections and the antibiotic resistance genes acquired by human pathogens each have an environmental origin. Recent work indicates that the function of these elements in their environmental reservoirs may be very distinct from the "weapon-shield" role they play in clinical settings. Changes in natural ecosystems, including the release of large amounts of antimicrobials, might alter the population dynamics of microorganisms, including selection of resistance, with consequences for human health that are difficult to predict.

1,519 citations


"Selection of resistant bacteria at ..." refers background in this paper

  • ...Whereas some resistance-conferring genes were most likely originally selected to serve metabolic functions and/or for signal trafficking or protection against competing antibiotic-producing bacteria [4], the recent worldwide enrichment and spread of highly resistant pathogenic bacteria in the micro-biosphere has largely been driven by human activities, including the extensive use and misuse of antibiotics in human and veterinary medicine and in agriculture [2,3,5,6,7]....

    [...]